I wonder if branch prediction can still hide the performance loss when the happy path checks become large/complex. Branch prediction is a very low level optimisation. And if the predictor is right you don't get everything for free. The CPU must still evaluate the condition, which takes resources, albeit it's no longer on the critical path. However I'd think the CPU would stall if it got too far ahead of the condition execution (ultimately all the code must execute before the program completes). Perhaps given the nature of Python, the checks would be so complex that in a tight loop they'd exert significant resource pressure?