We report 2 cases of cytomegalovirus-associated appendicitis in patients infected with human immunodeficiency virus and review 8 additional patients with cytomegalovirus appendicitis who were identified in the English-language literature. The clinical course and acute symptoms were very similar when these patients were compared with immunocompetent patients who had appendicitis. Laboratory findings and concomitant opportunistic infections set this disease process apart in human immunodeficiency virus–infected patients. Treatment was primarily surgery with adjunctive antiviral therapy. Accurate and timely diagnosis requires a high index of suspicion on the part of clinicians.