I did most of a Dark Souls playthrough with a PS3 controller that was breaking down. There's a tiny foam block on the inside that, after some years of abuse, will flatten out and trigger spurious inputs if some controls are pressed too hard. This caused an interesting challenge, since after panic-rolling, I would usually stand back up disarmed (d-pad right/left swaps that hand out for an alt item which was empty). It seemed kinda/sorta natural that way, and didn't know that wasn't a game mechanic (in this already ludicrously hard game) until I talked to some friends about it.

Edit: I made it through about 75% of the game like this.

I think it's the original Halo that asks you to look up or down during the tutorial, and then chooses your input method based on what you press.

Was a neat way of doing it.

what kinda games do you play???

StarCraft 2 coop has a mode called vertigo, which every 15 sec rotates your camera by a random angle... I had headache for 2 days...

Okay, not nearly the same, but I swear to god KH changes the fucking axis, target, and menu buttons each game, and my ass was fucking tired of it. So if a game changed inputs every save/startup I'd probably cry.