To access an array item, the type of the index variable must be size_t (or a type with the same size), otherwise the compiler produce less efficient machine code:
http://www.viva64.com/en/a/0050/

=> please keep Py_ssize_t type for i

(I didn't check for the specific case of Py_ssize_t: it's signed. Does GCC emit the most efficient machine code for it?)

diff -r 16c8278c03f6 Modules/_pickle.c
--- a/Modules/_pickle.c
+++ b/Modules/_pickle.c
@@ -4606,10 +4606,17 @@ static Py_ssize_t
 calc_binsize(char *bytes, int nbytes)
 {
     unsigned char *s = (unsigned char *)bytes;
-    Py_ssize_t i;
+    int i;
     size_t x = 0;
 
-    for (i = 0; i < nbytes && (size_t)i < sizeof(size_t); i++) {
+    if (nbytes > (int)sizeof(size_t)) {
+        for (i = (int)sizeof(size_t); i < nbytes; i++) {
+            if (s[i])
+                return -1;
+        }
+        nbytes = (int)sizeof(size_t);
+    }

Please add a comment here to explain that the first loop check for integer overflow, it's not obvious at the first read.

Does the Python implementation of pickle produce BINBYTES8? If not: why not?

Note: the patch is probably based on a private Mercurial revision, so it didn't get the [Review] button.