Fallout: New Vegas.
Love the game, it's potentially the best in the series. But I've hit the same game-ending glitch twice. Basically at a certain point an important faction decides to become completely hostile towards me despite me having positive faction rep and despite lots of tweaking with console commands to try to work around the problem.
I'd even restored a save from ten hours prior to triggering the bug and still had the problem once I progressed a quest line.
Super frustrating. I've experienced a lot of the early game multiple times but never gotten to the end of any of the major quest lines.