diff --git a/doc/source/whatsnew/v1.1.0.rst b/doc/source/whatsnew/v1.1.0.rst
index 73892da2cbf71..37fed6e5e3bd3 100644
--- a/doc/source/whatsnew/v1.1.0.rst
+++ b/doc/source/whatsnew/v1.1.0.rst
@@ -730,6 +730,7 @@ Indexing
 - Bug in :meth:`Series.__getitem__` allowing missing labels with ``np.ndarray``, :class:`Index`, :class:`Series` indexers but not ``list``, these now all raise ``KeyError`` (:issue:`33646`)
 - Bug in :meth:`DataFrame.truncate` and :meth:`Series.truncate` where index was assumed to be monotone increasing (:issue:`33756`)
 - Indexing with a list of strings representing datetimes failed on :class:`DatetimeIndex` or :class:`PeriodIndex`(:issue:`11278`)
+- Bug in :meth:`DataFrame.iloc` when setting values with list arguments would align row/column labels (:issue:`22046`)
 
 Missing
 ^^^^^^^
diff --git a/pandas/core/indexing.py b/pandas/core/indexing.py
index b857a59195695..5cd9c8db1a1b2 100644
--- a/pandas/core/indexing.py
+++ b/pandas/core/indexing.py
@@ -662,6 +662,10 @@ def __setitem__(self, key, value):
         indexer = self._get_setitem_indexer(key)
         self._has_valid_setitem_indexer(key)
 
+        if self.name == "iloc" and isinstance(value, (ABCSeries, ABCDataFrame)):
+            # Strip labels so as to not align with RHS
+            value = value._values.copy()
+
         iloc = self if self.name == "iloc" else self.obj.iloc
         iloc._setitem_with_indexer(indexer, value)
 
@@ -1717,7 +1721,8 @@ def isetter(loc, v):
 
                     for i, loc in enumerate(ilocs):
                         # setting with a list, re-coerces
-                        isetter(loc, value[:, i].tolist())
+                        # isetter(loc, value[:, i].tolist())
+                        isetter(loc, list(value[:, i]))
 
                 elif (
                     len(labels) == 1
diff --git a/pandas/tests/indexing/test_iloc.py b/pandas/tests/indexing/test_iloc.py
index c97cd81c84726..b9a4d3d10bff3 100644
--- a/pandas/tests/indexing/test_iloc.py
+++ b/pandas/tests/indexing/test_iloc.py
@@ -705,6 +705,15 @@ def test_iloc_setitem_categorical_updates_inplace(self):
         expected = pd.Categorical(["C", "B", "A"])
         tm.assert_categorical_equal(cat, expected)
 
+    def test_iloc_setitem_frame_no_alignment(self):
+        # GH 22046
+        # setting with iloc should not align labels
+        df = pd.DataFrame({"a": [1, 2], "b": [2, 3]}, index=[2, 1])
+        expected = df.copy()
+        df2 = pd.DataFrame({"b": [1, 2], "a": [2, 3]}, index=[1, 2])
+        df.iloc[:, [0, 1]] = df2.iloc[:, [0, 1]]
+        tm.assert_frame_equal(df, expected)
+
 
 class TestILocSetItemDuplicateColumns:
     def test_iloc_setitem_scalar_duplicate_columns(self):
@@ -733,3 +742,10 @@ def test_iloc_setitem_series_duplicate_columns(self):
         )
         df.iloc[:, 0] = df.iloc[:, 0].astype(np.float64)
         assert df.dtypes.iloc[2] == np.int64
+
+    def test_iloc_settime_frame_duplicate_columns(self):
+        idx = pd.MultiIndex.from_tuples((("a", "a"), ("a", "a")))
+        df = pd.DataFrame([[1, 1]], columns=idx)
+        expected = pd.DataFrame([[2, 2]], columns=idx)
+        df.iloc[:, [0, 1]] = expected.iloc[:, [0, 1]]
+        tm.assert_frame_equal(df, expected)
diff --git a/pandas/tests/indexing/test_indexing.py b/pandas/tests/indexing/test_indexing.py
index 51a7aa9bb586b..917741ef296f6 100644
--- a/pandas/tests/indexing/test_indexing.py
+++ b/pandas/tests/indexing/test_indexing.py
@@ -620,6 +620,20 @@ def test_astype_assignment(self):
         expected = DataFrame({"A": [1, 2, 3, 4]})
         tm.assert_frame_equal(df, expected)
 
+    def test_astype_assignment_nolabel(self):
+
+        # GH4312 (iloc)
+        df_orig = DataFrame(
+            [["1", "2", "3", ".4", 5, 6.0, "foo"]], columns=list("ABCDEFG")
+        )
+
+        df = df_orig.copy()
+        df.iloc[:, 0:2] = df.iloc[:, 0:2].values.astype(np.int64)
+        expected = DataFrame(
+            [[1, 2, "3", ".4", 5, 6.0, "foo"]], columns=list("ABCDEFG")
+        )
+        tm.assert_frame_equal(df, expected)
+
     def test_index_type_coercion(self):
 
         # GH 11836
@@ -716,27 +730,19 @@ def test_rhs_alignment(self):
         # GH8258, tests that both rows & columns are aligned to what is
         # assigned to. covers both uniform data-type & multi-type cases
         def run_tests(df, rhs, right):
-            # label, index, slice
-            lbl_one, idx_one, slice_one = list("bcd"), [1, 2, 3], slice(1, 4)
-            lbl_two, idx_two, slice_two = ["joe", "jolie"], [1, 2], slice(1, 3)
+            # labels
+            lbl_one = list("bcd")
+            lbl_two = ["joe", "jolie"]
 
             left = df.copy()
             left.loc[lbl_one, lbl_two] = rhs
             tm.assert_frame_equal(left, right)
 
-            left = df.copy()
-            left.iloc[idx_one, idx_two] = rhs
-            tm.assert_frame_equal(left, right)
-
-            left = df.copy()
-            left.iloc[slice_one, slice_two] = rhs
-            tm.assert_frame_equal(left, right)
-
         xs = np.arange(20).reshape(5, 4)
         cols = ["jim", "joe", "jolie", "joline"]
         df = DataFrame(xs, columns=cols, index=list("abcde"))
 
-        # right hand side; permute the indices and multiplpy by -2
+        # right hand side; permute the indices and multiply by -2
         rhs = -2 * df.iloc[3:0:-1, 2:0:-1]
 
         # expected `right` result; just multiply by -2