diff --git a/python/google/protobuf/internal/api_implementation.cc b/python/google/protobuf/internal/api_implementation.cc
index 6532a81405..802322424e 100644
--- a/python/google/protobuf/internal/api_implementation.cc
+++ b/python/google/protobuf/internal/api_implementation.cc
@@ -28,6 +28,7 @@
 // (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE
 // OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 namespace google {
diff --git a/python/google/protobuf/internal/reflection_test.py b/python/google/protobuf/internal/reflection_test.py
index 035ef6d614..66dd0c710a 100644
--- a/python/google/protobuf/internal/reflection_test.py
+++ b/python/google/protobuf/internal/reflection_test.py
@@ -37,6 +37,7 @@ import copy
 import gc
 import operator
 import struct
+import sys
 import warnings
 import unittest
 
@@ -376,7 +377,8 @@ class ReflectionTest(unittest.TestCase):
     self.assertRaises(TypeError, setattr, proto, 'optional_float', 'foo')
     self.assertRaises(TypeError, setattr, proto, 'optional_double', 'foo')
     # TODO(jieluo): Fix type checking difference for python and c extension
-    if api_implementation.Type() == 'python':
+    if (api_implementation.Type() == 'python' or
+        (sys.version_info.major, sys.version_info.minor) >= (3, 10)):
       self.assertRaises(TypeError, setattr, proto, 'optional_bool', 1.1)
     else:
       proto.optional_bool = 1.1
diff --git a/python/google/protobuf/proto_api.h b/python/google/protobuf/proto_api.h
index 2e2156a56e..9969a91f44 100644
--- a/python/google/protobuf/proto_api.h
+++ b/python/google/protobuf/proto_api.h
@@ -45,6 +45,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_PROTO_API_H__
 #define GOOGLE_PROTOBUF_PYTHON_PROTO_API_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/descriptor_database.h>
diff --git a/python/google/protobuf/pyext/descriptor.cc b/python/google/protobuf/pyext/descriptor.cc
index bc49e91b92..2101c2982e 100644
--- a/python/google/protobuf/pyext/descriptor.cc
+++ b/python/google/protobuf/pyext/descriptor.cc
@@ -32,6 +32,7 @@
 
 #include <google/protobuf/pyext/descriptor.h>
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 #include <frameobject.h>
 
diff --git a/python/google/protobuf/pyext/descriptor.h b/python/google/protobuf/pyext/descriptor.h
index b99209dd19..d97e2f8103 100644
--- a/python/google/protobuf/pyext/descriptor.h
+++ b/python/google/protobuf/pyext/descriptor.h
@@ -33,6 +33,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/descriptor.h>
diff --git a/python/google/protobuf/pyext/descriptor_containers.cc b/python/google/protobuf/pyext/descriptor_containers.cc
index b084f5b812..4caff6941a 100644
--- a/python/google/protobuf/pyext/descriptor_containers.cc
+++ b/python/google/protobuf/pyext/descriptor_containers.cc
@@ -49,6 +49,7 @@
 // because the Python API is based on C, and does not play well with C++
 // inheritance.
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/descriptor.h>
diff --git a/python/google/protobuf/pyext/descriptor_containers.h b/python/google/protobuf/pyext/descriptor_containers.h
index 4e05c58e2b..cf2cf4ad0b 100644
--- a/python/google/protobuf/pyext/descriptor_containers.h
+++ b/python/google/protobuf/pyext/descriptor_containers.h
@@ -34,6 +34,7 @@
 // Mappings and Sequences of descriptors.
 // They implement containers like fields_by_name, EnumDescriptor.values...
 // See descriptor_containers.cc for more description.
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 namespace google {
diff --git a/python/google/protobuf/pyext/descriptor_database.h b/python/google/protobuf/pyext/descriptor_database.h
index d2d9f8e506..3bc99e7dbc 100644
--- a/python/google/protobuf/pyext/descriptor_database.h
+++ b/python/google/protobuf/pyext/descriptor_database.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_DATABASE_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_DATABASE_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/descriptor_database.h>
diff --git a/python/google/protobuf/pyext/descriptor_pool.cc b/python/google/protobuf/pyext/descriptor_pool.cc
index 5ec6269cd4..f6bdb6e4c8 100644
--- a/python/google/protobuf/pyext/descriptor_pool.cc
+++ b/python/google/protobuf/pyext/descriptor_pool.cc
@@ -32,6 +32,7 @@
 
 #include <unordered_map>
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/descriptor.pb.h>
diff --git a/python/google/protobuf/pyext/descriptor_pool.h b/python/google/protobuf/pyext/descriptor_pool.h
index 48658d3e88..5d3c3a95cc 100644
--- a/python/google/protobuf/pyext/descriptor_pool.h
+++ b/python/google/protobuf/pyext/descriptor_pool.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_POOL_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_DESCRIPTOR_POOL_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <unordered_map>
diff --git a/python/google/protobuf/pyext/extension_dict.h b/python/google/protobuf/pyext/extension_dict.h
index c9da443161..a0581941bd 100644
--- a/python/google/protobuf/pyext/extension_dict.h
+++ b/python/google/protobuf/pyext/extension_dict.h
@@ -34,6 +34,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_EXTENSION_DICT_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_EXTENSION_DICT_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <memory>
diff --git a/python/google/protobuf/pyext/field.h b/python/google/protobuf/pyext/field.h
index 7b4660cab5..f9f94c4983 100644
--- a/python/google/protobuf/pyext/field.h
+++ b/python/google/protobuf/pyext/field.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_FIELD_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_FIELD_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 namespace google {
diff --git a/python/google/protobuf/pyext/map_container.h b/python/google/protobuf/pyext/map_container.h
index 842602e79f..e14136efab 100644
--- a/python/google/protobuf/pyext/map_container.h
+++ b/python/google/protobuf/pyext/map_container.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_MAP_CONTAINER_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_MAP_CONTAINER_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <cstdint>
diff --git a/python/google/protobuf/pyext/message.h b/python/google/protobuf/pyext/message.h
index 29af255154..b17daa5806 100644
--- a/python/google/protobuf/pyext/message.h
+++ b/python/google/protobuf/pyext/message.h
@@ -34,6 +34,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_MESSAGE_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_MESSAGE_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <cstdint>
diff --git a/python/google/protobuf/pyext/message_factory.cc b/python/google/protobuf/pyext/message_factory.cc
index 30dfab88dc..5098379f35 100644
--- a/python/google/protobuf/pyext/message_factory.cc
+++ b/python/google/protobuf/pyext/message_factory.cc
@@ -30,6 +30,7 @@
 
 #include <unordered_map>
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/dynamic_message.h>
diff --git a/python/google/protobuf/pyext/message_factory.h b/python/google/protobuf/pyext/message_factory.h
index 515c29cdb8..7dfe425dd5 100644
--- a/python/google/protobuf/pyext/message_factory.h
+++ b/python/google/protobuf/pyext/message_factory.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_MESSAGE_FACTORY_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_MESSAGE_FACTORY_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <unordered_map>
diff --git a/python/google/protobuf/pyext/message_module.cc b/python/google/protobuf/pyext/message_module.cc
index 971d2bad70..a0806a3160 100644
--- a/python/google/protobuf/pyext/message_module.cc
+++ b/python/google/protobuf/pyext/message_module.cc
@@ -28,6 +28,7 @@
 // (INCLUDING NEGLIGENCE OR OTHERWISE) ARISING IN ANY WAY OUT OF THE USE
 // OF THIS SOFTWARE, EVEN IF ADVISED OF THE POSSIBILITY OF SUCH DAMAGE.
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <google/protobuf/message_lite.h>
diff --git a/python/google/protobuf/pyext/repeated_composite_container.h b/python/google/protobuf/pyext/repeated_composite_container.h
index e241827ef5..30536eabd4 100644
--- a/python/google/protobuf/pyext/repeated_composite_container.h
+++ b/python/google/protobuf/pyext/repeated_composite_container.h
@@ -34,6 +34,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_REPEATED_COMPOSITE_CONTAINER_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_REPEATED_COMPOSITE_CONTAINER_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <memory>
diff --git a/python/google/protobuf/pyext/repeated_scalar_container.h b/python/google/protobuf/pyext/repeated_scalar_container.h
index f9f0ea8f31..372b6f0a35 100644
--- a/python/google/protobuf/pyext/repeated_scalar_container.h
+++ b/python/google/protobuf/pyext/repeated_scalar_container.h
@@ -34,6 +34,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_REPEATED_SCALAR_CONTAINER_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_REPEATED_SCALAR_CONTAINER_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <memory>
diff --git a/python/google/protobuf/pyext/scoped_pyobject_ptr.h b/python/google/protobuf/pyext/scoped_pyobject_ptr.h
index 6f7fc29813..985df2c3bb 100644
--- a/python/google/protobuf/pyext/scoped_pyobject_ptr.h
+++ b/python/google/protobuf/pyext/scoped_pyobject_ptr.h
@@ -35,6 +35,7 @@
 
 #include <google/protobuf/stubs/common.h>
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 namespace google {
 namespace protobuf {
diff --git a/python/google/protobuf/pyext/unknown_fields.cc b/python/google/protobuf/pyext/unknown_fields.cc
index 5dbcd88568..31926c8554 100644
--- a/python/google/protobuf/pyext/unknown_fields.cc
+++ b/python/google/protobuf/pyext/unknown_fields.cc
@@ -30,6 +30,7 @@
 
 #include <google/protobuf/pyext/unknown_fields.h>
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 #include <set>
 #include <memory>
diff --git a/python/google/protobuf/pyext/unknown_fields.h b/python/google/protobuf/pyext/unknown_fields.h
index 94d55e148d..e7b0b35c41 100644
--- a/python/google/protobuf/pyext/unknown_fields.h
+++ b/python/google/protobuf/pyext/unknown_fields.h
@@ -31,6 +31,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_CPP_UNKNOWN_FIELDS_H__
 #define GOOGLE_PROTOBUF_PYTHON_CPP_UNKNOWN_FIELDS_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 #include <memory>
diff --git a/python/google/protobuf/python_protobuf.h b/python/google/protobuf/python_protobuf.h
index 8db1ffb750..4fcf065404 100644
--- a/python/google/protobuf/python_protobuf.h
+++ b/python/google/protobuf/python_protobuf.h
@@ -36,6 +36,7 @@
 #ifndef GOOGLE_PROTOBUF_PYTHON_PYTHON_PROTOBUF_H__
 #define GOOGLE_PROTOBUF_PYTHON_PYTHON_PROTOBUF_H__
 
+#define PY_SSIZE_T_CLEAN
 #include <Python.h>
 
 namespace google {