When George and Ira are in the kitchen for the first time, there's a close-up shot of George's glass to show how dirty it is. After George asks Ira to kill him, if you look at his glass you can see it becomes spotlessly clean.
When George and Ira are at George's house and Laura shows up, behind them you can see pool cleaners cleaning the pool. However, when it switches to the security camera, there is no one cleaning the pool.
When Ira is playing George his playlist you can see he clicks on the second song but when it flicks back the song highlighted is way further down. It flicks back again and the highlight is back to the second spot.
When George enters Ira's house for Thanksgiving dinner, he points out to Leo that they have the poster for his movie "Re-Do" (the baby movie) hanging on the wall. During the scene while George and Leo are discussing the movie, the poster behind Leo switches from "Re-Do" to another film.
When James Taylor is finishing his last song at the MySpace function, you can see he is sitting on a stool, alone, on stage. When he finishes and stands up, his back-up singers from earlier have suddenly returned.
The MySpace gig takes place far enough away that George and Ira take a private plane. At the end of scene, he gets two girls to go back to his place. But at the end of those scenes the girls leave on their own, apparently left to their own resources to get back.
Clarke invites Ira and George to watch the football finals from Australia, in a scene taking place in December. Australian football finals are played in September. In case of play-offs they may drag out into early October, but no later.
The ending disclaimer states that no real persons are depicted, yet many people including Ray Romano and Sarah Silverman appear as themselves during the course of the movie and are identified by their real names.
In the kitchen/medicine scene, in the last part of the scene, someone can be seen moving outside the window. George mentions his workers and later in the movie we see more evidence that he has lots of servants and people working for him, so the person outside the window was probably a servant.
The goof items below may give away important plot points.
During the final scene between George and Ira sitting at the table at Otto's, the woman in the background (behind Ira) can be seen at the counter several times. Also, by the end of the scene, she leaves, but at the final shot, she suddenly returns to the counter.