From Skyrim it has to be Cicero. Before I started the Dark Brotherhood I was just walking around and I found this farm and this guy sitting outside. He told me that he wanted me to get rid of this jester for him by talking to the guard by his house. Well I decided to try to kill him. But when he only got on his knees I was like Fuck! So I ended up going to jail. But when I came back to that spot I told the town guard that Cicero stole something. Then when I saw Cicero in the Dark Brotherhood hideout I talked to him and he got really pissed off at me.
From Oblivion though on the Shivering Isles it would have to be Sheogorath. Just because he's insane!
I met a really funny npc in Morthal. He dare'd me at a brawl and when i won he said the we where the bestest of friends!! Hahaha. I was just finished with helping the people in the villiga by then and i was going back to the jarl to become his thane.. And when i started to chat with the jarl of Morthal the other guy rushes in to interrupt my conversation with the jarl, and just says; -I'm youre best friend!
I laughed sooo hard when this happend that i was decorating my livingroom floor with milk! haha crazy easter eggs...