Granulomatous appendicitis is an enigmatic entity. Purported causes include Crohn's disease, foreign body reactions, sarcoidosis, and infectious agents; however, most cases remain idiopathic. Yersinia enterocolitica (YE) and Y. pseudotuberculosis (YP) have been implicated as causes of appendicitis, ileocolitis, and mesenteric adenitis. The authors examined the potential role of YE and YP in granulomatous appendicitis using histologic and molecular methods. Forty cases of granulomatous appendicitis were evaluated for histologic features including transmural inflammation, number and character of granulomas, and mucosal changes. Twort Gram, Grocott methenamine-silver (GMS), and Ziehl-Neelsen stains were evaluated, and polymerase chain reaction (PCR) analysis was performed to identify pathogenic YP and YE. Twenty-five percent (10 of 40) of the cases were positive for pathogenic Yersinia by PCR (four YE, four YP, and two with both species). Prominent histologic features included epithelioid granulomas with lymphoid cuffing, transmural inflammation with lymphoid aggregates, mucosal ulceration, and cryptitis. One Yersinia-positive case contained mural Gram-negative bacilli; fungal and acid-fast bacilli stains were all negative. Except for one culture-negative case, serologies and cultures were not done or results were unavailable. Two Yersinia-positive patients were diagnosed subsequently with Crohn's disease, suggesting a possible relationship between the two entities. No other patients developed significant sequelae. YE and YP are important causes of granulomatous appendicitis, and Yersinia infection may mimic Crohn's disease. No histologic features distinguish reliably between Yersinia species, or between Yersinia-positive and Yersinia-negative cases. Because special stains and cultures are often not diagnostic, PCR analysis is an excellent technique for the diagnosis of Yersinia.