Usually it's the people or the personalities involved.
One of the prime ways to ruin a campaign is to jerk the rug out from under me and change things about my character with no consultation or warning.
Two campaigns were ruined for me on the first night.
1. I create a superhero who is also a cop. He's an undercover vice cop, knee-deep in the scum of the city. Which also allows him to disappear into his costumed persona for long periods of time with no real questions asked.
GM reads and approves the character background.
Opening night, the GM tells me that my character has been transferred to a desk job in Missing Persons (because this suits his first plotline) where I'm lucky to be able to take a lunch without someone asking where I am, much less being able to disappear for three days because I've been locked in a makeshift prison cell in the sewers. I am soon fired from the police force.
2. Knowing we are doing a game that is very dark grey in tone, I create a character who has no real use for the humans around him. Any friends he has are temporary means to an end, and this includes any girlfriends he has. The emotion of 'love', since it is prettty much defined as 'caring about another person more than yourself' is utterly alien to him.
GM reads and approves the character background.
The GM, unknown to me, has a personality quirk: Women Can Do No Wrong. Literally. They can't be bad people, ever, nor can he stand to see them treated badly. Within two hours of the first night, I'm told I really do love my girlfriend and want to stay exclusively with her.