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Comic-Con International has served as the setting for Mark Hamill's Comic Book: The Movie, and for an episode of the HBO television series Entourage, the latter of which, while set at the event, was not filmed there.

Comic-Con also served as an excuse for the fictional characters Seth Cohen and Ryan Atwood's trip to Tijuana, Mexico in the first season of TV series The O. C.

The convention also featured prominently as a setting for the Numb3rs episode " Graphic ".

In Season 4 of Beauty and the Geek, an episode was featured where the contestants traveled to Comic-Con 07 and were given a challenge to create their own superheroes.

In an episode of Punk'd, Hilary Swank gets Punk'd after an " attack from talking robot.

" In Season 5, episode six of the Showtime show Weeds, attendees from Comic Con 2009 are seen in Silas and Doug's medicinal marijuana club.