diff --git a/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst b/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst
new file mode 100644
index 00000000000000..b697658cf3aaa3
--- /dev/null
+++ b/Misc/NEWS.d/next/Build/2021-11-24-17-14-06.bpo-45881.GTXXLk.rst
@@ -0,0 +1,2 @@
+``setup.py`` now uses ``CC`` from environment first to discover multiarch
+and cross compile paths.
diff --git a/setup.py b/setup.py
index 9a5887b59ffc41..c6023e1ab6353e 100644
--- a/setup.py
+++ b/setup.py
@@ -65,6 +65,9 @@ def get_platform():
 MACOS = (HOST_PLATFORM == 'darwin')
 AIX = (HOST_PLATFORM.startswith('aix'))
 VXWORKS = ('vxworks' in HOST_PLATFORM)
+CC = os.environ.get("CC")
+if not CC:
+    CC = sysconfig.get_config_var("CC")
 
 
 SUMMARY = """
@@ -443,6 +446,9 @@ def set_compiler_executables(self):
 
     def build_extensions(self):
         self.set_srcdir()
+        self.set_compiler_executables()
+        self.configure_compiler()
+        self.init_inc_lib_dirs()
 
         # Detect which modules should be compiled
         self.detect_modules()
@@ -451,7 +457,6 @@ def build_extensions(self):
 
         self.update_sources_depends()
         mods_built, mods_disabled = self.remove_configured_extensions()
-        self.set_compiler_executables()
 
         build_ext.build_extensions(self)
 
@@ -631,12 +636,11 @@ def check_extension_import(self, ext):
     def add_multiarch_paths(self):
         # Debian/Ubuntu multiarch support.
         # https://wiki.ubuntu.com/MultiarchSpec
-        cc = sysconfig.get_config_var('CC')
         tmpfile = os.path.join(self.build_temp, 'multiarch')
         if not os.path.exists(self.build_temp):
             os.makedirs(self.build_temp)
         ret = run_command(
-            '%s -print-multiarch > %s 2> /dev/null' % (cc, tmpfile))
+            '%s -print-multiarch > %s 2> /dev/null' % (CC, tmpfile))
         multiarch_path_component = ''
         try:
             if ret == 0:
@@ -675,11 +679,10 @@ def add_multiarch_paths(self):
             os.unlink(tmpfile)
 
     def add_cross_compiling_paths(self):
-        cc = sysconfig.get_config_var('CC')
         tmpfile = os.path.join(self.build_temp, 'ccpaths')
         if not os.path.exists(self.build_temp):
             os.makedirs(self.build_temp)
-        ret = run_command('%s -E -v - </dev/null 2>%s 1>/dev/null' % (cc, tmpfile))
+        ret = run_command('%s -E -v - </dev/null 2>%s 1>/dev/null' % (CC, tmpfile))
         is_gcc = False
         is_clang = False
         in_incdirs = False
@@ -1783,9 +1786,6 @@ def detect_uuid(self):
             self.missing.append('_uuid')
 
     def detect_modules(self):
-        self.configure_compiler()
-        self.init_inc_lib_dirs()
-
         self.detect_simple_extensions()
         if TEST_EXTENSIONS:
             self.detect_test_extensions()