diff --git a/src/compiler/checker.ts b/src/compiler/checker.ts
index c6a9f7e75a633..3d9829345eb73 100644
--- a/src/compiler/checker.ts
+++ b/src/compiler/checker.ts
@@ -12849,9 +12849,17 @@ namespace ts {
 
         function getConditionalFlowTypeOfType(type: Type, node: Node) {
             let constraints: Type[] | undefined;
+            let covariant = true;
             while (node && !isStatement(node) && node.kind !== SyntaxKind.JSDocComment) {
                 const parent = node.parent;
-                if (parent.kind === SyntaxKind.ConditionalType && node === (<ConditionalTypeNode>parent).trueType) {
+                // only consider variance flipped by parameter locations - `keyof` types would usually be considered variance inverting, but
+                // often get used in indexed accesses where they behave sortof invariantly, but our checking is lax
+                if (parent.kind === SyntaxKind.Parameter) {
+                    covariant = !covariant;
+                }
+                // Always substitute on type parameters, regardless of variance, since even
+                // in contravarrying positions, they may be reliant on subtuted constraints to be valid
+                if ((covariant || type.flags & TypeFlags.TypeParameter) && parent.kind === SyntaxKind.ConditionalType && node === (<ConditionalTypeNode>parent).trueType) {
                     const constraint = getImpliedConstraint(type, (<ConditionalTypeNode>parent).checkType, (<ConditionalTypeNode>parent).extendsType);
                     if (constraint) {
                         constraints = append(constraints, constraint);
diff --git a/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.js b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.js
new file mode 100644
index 0000000000000..b3e236ff9cd7b
--- /dev/null
+++ b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.js
@@ -0,0 +1,53 @@
+//// [callOfConditionalTypeWithConcreteBranches.ts]
+type Q<T> = number extends T ? (n: number) => void : never;
+function fn<T>(arg: Q<T>) {
+  // Expected: OK
+  // Actual: Cannot convert 10 to number & T
+  arg(10);
+}
+// Legal invocations are not problematic
+fn<string | number>(m => m.toFixed());
+fn<number>(m => m.toFixed());
+
+// Ensure the following real-world example that relies on substitution still works
+type ExtractParameters<T> = "parameters" extends keyof T
+  // The above allows "parameters" to index `T` since all later
+  // instances are actually implicitly `"parameters" & keyof T`
+  ?  {
+        [K in keyof T["parameters"]]: T["parameters"][K];
+      }[keyof T["parameters"]]
+  : {};
+
+// Original example, but with inverted variance
+type Q2<T> = number extends T ? (cb: (n: number) => void) => void : never;
+function fn2<T>(arg: Q2<T>) {
+  function useT(_arg: T): void {}
+  // Expected: OK
+  arg(arg => useT(arg));
+}
+// Legal invocations are not problematic
+fn2<string | number>(m => m(42));
+fn2<number>(m => m(42));
+
+// webidl-conversions example where substituion must occur, despite contravariance of the position
+// due to the invariant usage in `Parameters`
+
+type X<V> = V extends (...args: any[]) => any ? (...args: Parameters<V>) => void : Function;
+
+//// [callOfConditionalTypeWithConcreteBranches.js]
+function fn(arg) {
+    // Expected: OK
+    // Actual: Cannot convert 10 to number & T
+    arg(10);
+}
+// Legal invocations are not problematic
+fn(function (m) { return m.toFixed(); });
+fn(function (m) { return m.toFixed(); });
+function fn2(arg) {
+    function useT(_arg) { }
+    // Expected: OK
+    arg(function (arg) { return useT(arg); });
+}
+// Legal invocations are not problematic
+fn2(function (m) { return m(42); });
+fn2(function (m) { return m(42); });
diff --git a/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.symbols b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.symbols
new file mode 100644
index 0000000000000..dbed1d31aa944
--- /dev/null
+++ b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.symbols
@@ -0,0 +1,105 @@
+=== tests/cases/compiler/callOfConditionalTypeWithConcreteBranches.ts ===
+type Q<T> = number extends T ? (n: number) => void : never;
+>Q : Symbol(Q, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 0))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 7))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 7))
+>n : Symbol(n, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 32))
+
+function fn<T>(arg: Q<T>) {
+>fn : Symbol(fn, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 59))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 1, 12))
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 1, 15))
+>Q : Symbol(Q, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 0))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 1, 12))
+
+  // Expected: OK
+  // Actual: Cannot convert 10 to number & T
+  arg(10);
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 1, 15))
+}
+// Legal invocations are not problematic
+fn<string | number>(m => m.toFixed());
+>fn : Symbol(fn, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 59))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 7, 20))
+>m.toFixed : Symbol(Number.toFixed, Decl(lib.es5.d.ts, --, --))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 7, 20))
+>toFixed : Symbol(Number.toFixed, Decl(lib.es5.d.ts, --, --))
+
+fn<number>(m => m.toFixed());
+>fn : Symbol(fn, Decl(callOfConditionalTypeWithConcreteBranches.ts, 0, 59))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 8, 11))
+>m.toFixed : Symbol(Number.toFixed, Decl(lib.es5.d.ts, --, --))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 8, 11))
+>toFixed : Symbol(Number.toFixed, Decl(lib.es5.d.ts, --, --))
+
+// Ensure the following real-world example that relies on substitution still works
+type ExtractParameters<T> = "parameters" extends keyof T
+>ExtractParameters : Symbol(ExtractParameters, Decl(callOfConditionalTypeWithConcreteBranches.ts, 8, 29))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 11, 23))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 11, 23))
+
+  // The above allows "parameters" to index `T` since all later
+  // instances are actually implicitly `"parameters" & keyof T`
+  ?  {
+        [K in keyof T["parameters"]]: T["parameters"][K];
+>K : Symbol(K, Decl(callOfConditionalTypeWithConcreteBranches.ts, 15, 9))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 11, 23))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 11, 23))
+>K : Symbol(K, Decl(callOfConditionalTypeWithConcreteBranches.ts, 15, 9))
+
+      }[keyof T["parameters"]]
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 11, 23))
+
+  : {};
+
+// Original example, but with inverted variance
+type Q2<T> = number extends T ? (cb: (n: number) => void) => void : never;
+>Q2 : Symbol(Q2, Decl(callOfConditionalTypeWithConcreteBranches.ts, 17, 7))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 8))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 8))
+>cb : Symbol(cb, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 33))
+>n : Symbol(n, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 38))
+
+function fn2<T>(arg: Q2<T>) {
+>fn2 : Symbol(fn2, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 74))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 13))
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 16))
+>Q2 : Symbol(Q2, Decl(callOfConditionalTypeWithConcreteBranches.ts, 17, 7))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 13))
+
+  function useT(_arg: T): void {}
+>useT : Symbol(useT, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 29))
+>_arg : Symbol(_arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 22, 16))
+>T : Symbol(T, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 13))
+
+  // Expected: OK
+  arg(arg => useT(arg));
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 16))
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 24, 6))
+>useT : Symbol(useT, Decl(callOfConditionalTypeWithConcreteBranches.ts, 21, 29))
+>arg : Symbol(arg, Decl(callOfConditionalTypeWithConcreteBranches.ts, 24, 6))
+}
+// Legal invocations are not problematic
+fn2<string | number>(m => m(42));
+>fn2 : Symbol(fn2, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 74))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 27, 21))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 27, 21))
+
+fn2<number>(m => m(42));
+>fn2 : Symbol(fn2, Decl(callOfConditionalTypeWithConcreteBranches.ts, 20, 74))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 28, 12))
+>m : Symbol(m, Decl(callOfConditionalTypeWithConcreteBranches.ts, 28, 12))
+
+// webidl-conversions example where substituion must occur, despite contravariance of the position
+// due to the invariant usage in `Parameters`
+
+type X<V> = V extends (...args: any[]) => any ? (...args: Parameters<V>) => void : Function;
+>X : Symbol(X, Decl(callOfConditionalTypeWithConcreteBranches.ts, 28, 24))
+>V : Symbol(V, Decl(callOfConditionalTypeWithConcreteBranches.ts, 33, 7))
+>V : Symbol(V, Decl(callOfConditionalTypeWithConcreteBranches.ts, 33, 7))
+>args : Symbol(args, Decl(callOfConditionalTypeWithConcreteBranches.ts, 33, 23))
+>args : Symbol(args, Decl(callOfConditionalTypeWithConcreteBranches.ts, 33, 49))
+>Parameters : Symbol(Parameters, Decl(lib.es5.d.ts, --, --))
+>V : Symbol(V, Decl(callOfConditionalTypeWithConcreteBranches.ts, 33, 7))
+>Function : Symbol(Function, Decl(lib.es5.d.ts, --, --), Decl(lib.es5.d.ts, --, --))
+
diff --git a/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.types b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.types
new file mode 100644
index 0000000000000..2bee57b8fe796
--- /dev/null
+++ b/tests/baselines/reference/callOfConditionalTypeWithConcreteBranches.types
@@ -0,0 +1,99 @@
+=== tests/cases/compiler/callOfConditionalTypeWithConcreteBranches.ts ===
+type Q<T> = number extends T ? (n: number) => void : never;
+>Q : Q<T>
+>n : number
+
+function fn<T>(arg: Q<T>) {
+>fn : <T>(arg: Q<T>) => void
+>arg : Q<T>
+
+  // Expected: OK
+  // Actual: Cannot convert 10 to number & T
+  arg(10);
+>arg(10) : void
+>arg : Q<T>
+>10 : 10
+}
+// Legal invocations are not problematic
+fn<string | number>(m => m.toFixed());
+>fn<string | number>(m => m.toFixed()) : void
+>fn : <T>(arg: Q<T>) => void
+>m => m.toFixed() : (m: number) => string
+>m : number
+>m.toFixed() : string
+>m.toFixed : (fractionDigits?: number) => string
+>m : number
+>toFixed : (fractionDigits?: number) => string
+
+fn<number>(m => m.toFixed());
+>fn<number>(m => m.toFixed()) : void
+>fn : <T>(arg: Q<T>) => void
+>m => m.toFixed() : (m: number) => string
+>m : number
+>m.toFixed() : string
+>m.toFixed : (fractionDigits?: number) => string
+>m : number
+>toFixed : (fractionDigits?: number) => string
+
+// Ensure the following real-world example that relies on substitution still works
+type ExtractParameters<T> = "parameters" extends keyof T
+>ExtractParameters : ExtractParameters<T>
+
+  // The above allows "parameters" to index `T` since all later
+  // instances are actually implicitly `"parameters" & keyof T`
+  ?  {
+        [K in keyof T["parameters"]]: T["parameters"][K];
+      }[keyof T["parameters"]]
+  : {};
+
+// Original example, but with inverted variance
+type Q2<T> = number extends T ? (cb: (n: number) => void) => void : never;
+>Q2 : Q2<T>
+>cb : (n: number) => void
+>n : number
+
+function fn2<T>(arg: Q2<T>) {
+>fn2 : <T>(arg: Q2<T>) => void
+>arg : Q2<T>
+
+  function useT(_arg: T): void {}
+>useT : (_arg: T) => void
+>_arg : T
+
+  // Expected: OK
+  arg(arg => useT(arg));
+>arg(arg => useT(arg)) : void
+>arg : Q2<T>
+>arg => useT(arg) : (arg: T & number) => void
+>arg : T & number
+>useT(arg) : void
+>useT : (_arg: T) => void
+>arg : T & number
+}
+// Legal invocations are not problematic
+fn2<string | number>(m => m(42));
+>fn2<string | number>(m => m(42)) : void
+>fn2 : <T>(arg: Q2<T>) => void
+>m => m(42) : (m: (n: number) => void) => void
+>m : (n: number) => void
+>m(42) : void
+>m : (n: number) => void
+>42 : 42
+
+fn2<number>(m => m(42));
+>fn2<number>(m => m(42)) : void
+>fn2 : <T>(arg: Q2<T>) => void
+>m => m(42) : (m: (n: number) => void) => void
+>m : (n: number) => void
+>m(42) : void
+>m : (n: number) => void
+>42 : 42
+
+// webidl-conversions example where substituion must occur, despite contravariance of the position
+// due to the invariant usage in `Parameters`
+
+type X<V> = V extends (...args: any[]) => any ? (...args: Parameters<V>) => void : Function;
+>X : X<V>
+>args : any[]
+>args : Parameters<V>
+
diff --git a/tests/cases/compiler/callOfConditionalTypeWithConcreteBranches.ts b/tests/cases/compiler/callOfConditionalTypeWithConcreteBranches.ts
new file mode 100644
index 0000000000000..91b236ef61fbd
--- /dev/null
+++ b/tests/cases/compiler/callOfConditionalTypeWithConcreteBranches.ts
@@ -0,0 +1,34 @@
+type Q<T> = number extends T ? (n: number) => void : never;
+function fn<T>(arg: Q<T>) {
+  // Expected: OK
+  // Actual: Cannot convert 10 to number & T
+  arg(10);
+}
+// Legal invocations are not problematic
+fn<string | number>(m => m.toFixed());
+fn<number>(m => m.toFixed());
+
+// Ensure the following real-world example that relies on substitution still works
+type ExtractParameters<T> = "parameters" extends keyof T
+  // The above allows "parameters" to index `T` since all later
+  // instances are actually implicitly `"parameters" & keyof T`
+  ?  {
+        [K in keyof T["parameters"]]: T["parameters"][K];
+      }[keyof T["parameters"]]
+  : {};
+
+// Original example, but with inverted variance
+type Q2<T> = number extends T ? (cb: (n: number) => void) => void : never;
+function fn2<T>(arg: Q2<T>) {
+  function useT(_arg: T): void {}
+  // Expected: OK
+  arg(arg => useT(arg));
+}
+// Legal invocations are not problematic
+fn2<string | number>(m => m(42));
+fn2<number>(m => m(42));
+
+// webidl-conversions example where substituion must occur, despite contravariance of the position
+// due to the invariant usage in `Parameters`
+
+type X<V> = V extends (...args: any[]) => any ? (...args: Parameters<V>) => void : Function;
\ No newline at end of file