diff --git a/PCbuild/pyproject.props b/PCbuild/pyproject.props
index dbdb6b743bea37..17abfa85201a90 100644
--- a/PCbuild/pyproject.props
+++ b/PCbuild/pyproject.props
@@ -53,6 +53,7 @@
     <ClCompile>
       <AdditionalIncludeDirectories>$(PySourcePath)Include;$(PySourcePath)Include\internal;$(PySourcePath)Include\internal\mimalloc;$(GeneratedPyConfigDir);$(PySourcePath)PC;%(AdditionalIncludeDirectories)</AdditionalIncludeDirectories>
       <PreprocessorDefinitions>WIN32;$(_Py3NamePreprocessorDefinition);$(_PlatformPreprocessorDefinition)$(_DebugPreprocessorDefinition)$(_PyStatsPreprocessorDefinition)$(_PydPreprocessorDefinition)%(PreprocessorDefinitions)</PreprocessorDefinitions>
+      <PreprocessorDefinitions Condition="'$(SupportPGO)' and ($(Configuration) == 'PGInstrument' or $(Configuration) == 'PGUpdate')">_Py_USING_PGO=1;%(PreprocessorDefinitions)</PreprocessorDefinitions>
 
       <Optimization>MaxSpeed</Optimization>
       <IntrinsicFunctions>true</IntrinsicFunctions>
diff --git a/Python/ceval.c b/Python/ceval.c
index 1e4f1f3af20aca..c6a7a0f841f027 100644
--- a/Python/ceval.c
+++ b/Python/ceval.c
@@ -764,6 +764,23 @@ _PyObjectArray_Free(PyObject **array, PyObject **scratch)
 #define PY_EVAL_C_STACK_UNITS 2
 
 
+/* _PyEval_EvalFrameDefault is too large to optimize for speed with PGO on MSVC
+   when the JIT is enabled or GIL is disabled. Disable that optimization around
+   this function only. If this is fixed upstream, we should gate this on the
+   version of MSVC.
+ */
+#if (defined(_MSC_VER) && \
+     defined(_Py_USING_PGO) && \
+     (defined(_Py_JIT) || \
+      defined(Py_GIL_DISABLED)))
+#define DO_NOT_OPTIMIZE_INTERP_LOOP
+#endif
+
+#ifdef DO_NOT_OPTIMIZE_INTERP_LOOP
+#  pragma optimize("t", off)
+/* This setting is reversed below following _PyEval_EvalFrameDefault */
+#endif
+
 #ifdef Py_TAIL_CALL_INTERP
 #include "opcode_targets.h"
 #include "generated_cases.c.h"
@@ -986,6 +1003,10 @@ _PyEval_EvalFrameDefault(PyThreadState *tstate, _PyInterpreterFrame *frame, int
     return NULL;
 }
 
+#ifdef DO_NOT_OPTIMIZE_INTERP_LOOP
+#  pragma optimize("", on)
+#endif
+
 #if defined(__GNUC__)
 #  pragma GCC diagnostic pop
 #elif defined(_MSC_VER) /* MS_WINDOWS */