diff --git a/include/pybind11/detail/common.h b/include/pybind11/detail/common.h
index 6e295fd2f..9acf10466 100644
--- a/include/pybind11/detail/common.h
+++ b/include/pybind11/detail/common.h
@@ -323,6 +323,15 @@ PYBIND11_WARNING_POP
 #    define PYBIND11_HAS_U8STRING
 #endif
 
+// See description of PR #4246:
+#if !defined(NDEBUG) && !defined(PY_ASSERT_GIL_HELD_INCREF_DECREF)                                \
+    && !(defined(PYPY_VERSION)                                                                    \
+         && defined(_MSC_VER)) /* PyPy Windows: pytest hangs indefinitely at the end of the       \
+                                  process (see PR #4268) */                                       \
+    && !defined(PYBIND11_ASSERT_GIL_HELD_INCREF_DECREF)
+#    define PYBIND11_ASSERT_GIL_HELD_INCREF_DECREF
+#endif
+
 // #define PYBIND11_STR_LEGACY_PERMISSIVE
 // If DEFINED, pybind11::str can hold PyUnicodeObject or PyBytesObject
 //             (probably surprising and never documented, but this was the
diff --git a/include/pybind11/pytypes.h b/include/pybind11/pytypes.h
index 328287931..56e0423ac 100644
--- a/include/pybind11/pytypes.h
+++ b/include/pybind11/pytypes.h
@@ -249,6 +249,11 @@ public:
     const handle &inc_ref() const & {
 #ifdef PYBIND11_HANDLE_REF_DEBUG
         inc_ref_counter(1);
+#endif
+#if defined(PYBIND11_ASSERT_GIL_HELD_INCREF_DECREF)
+        if (m_ptr != nullptr && !PyGILState_Check()) {
+            throw std::runtime_error("pybind11::handle::inc_ref() PyGILState_Check() failure.");
+        }
 #endif
         Py_XINCREF(m_ptr);
         return *this;
@@ -260,6 +265,11 @@ public:
         this function automatically. Returns a reference to itself.
     \endrst */
     const handle &dec_ref() const & {
+#if defined(PYBIND11_ASSERT_GIL_HELD_INCREF_DECREF)
+        if (m_ptr != nullptr && !PyGILState_Check()) {
+            throw std::runtime_error("pybind11::handle::dec_ref() PyGILState_Check() failure.");
+        }
+#endif
         Py_XDECREF(m_ptr);
         return *this;
     }