Note that issue8425a.diff leaves small_set.difference_update(large_dict) unoptimized:

$ ./python.exe -m timeit -s "s = {1}; l = dict.fromkeys(range(1000));" "s.difference_update(l)"
1000 loops, best of 3: 842 usec per loop
$ ./python.exe -m timeit -s "s = {1}; l = dict.fromkeys(range(1000));" "s.difference(l)"
100000 loops, best of 3: 13.2 usec per loop

It would be easy to add an extra type check, but I noticed that small_set.difference_update(large_dict.viewkeys()) is not optimized either:

$ ./python.exe -m timeit -s "s = {1}; l = dict.fromkeys(range(1000));" "s.difference(l.viewkeys())"
1000 loops, best of 3: 842 usec per loop

It would be nice if there was a uniform C-API that would allow to uniformly check that an object supports O(1) lookup and invoke such lookup efficiently.  I don't think such C-API exists at the moment.

I would like to hear what others have to say before adding optimizations  to the patch that go beyond the scope of this issue.