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Gimatti's film career has combined prominent supporting roles with quirky leads. He received an Academy Award nomination for Best Supporting actor for Cinderella Man (2005) as manager Joe Gould. His performances in American Splendor (as graphic novelist Harvey Pekar) and Sideways garnered additional acclaim. Other film credits include Lady in the Water, Tim Burton's Planet of the Apes (as an orangutan), Paycheck, The Illusionist, Deconstructiong Harry, and Fred Claus (as Santa Claus). On television, Giamatti played John Adams in the HBO miniseries and has guest starred on Homicide: Life on the Streets and King of the Hill.