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Rosie O'Donnell appeared in the South Park episode, "Trapper Keeper." She helps to unwittingly defeat the evil Trapper Keeper by annoying it, being absorbed, and then half dissolved inside it she caused it indigestion. She was also seen in "200" and "201" with all the other celebrities that were mad at the town. In Principal Victoria's office, there is a photo of her and Rosie.
- Throughout the episode, she is constantly believed by the rest of the cast to be some sort of hideous blob monster, such as when one of the security guards believed there were two monsters when she stood near the mutant Cartman/Trapper Keeper hybrid.