Although appendectomy is often the first surgical procedure in patients with Crohn's disease (CD), only few data exist on appendiceal CD. The aim of this study was to analyze appendices of CD patients undergoing surgery. We analyzed 149 specimens from consecutive patients with CD who underwent primary right ileocolonic or (sub)total colonic resection. The appendix was present in 90 resection specimens. Histologic findings were compared with those of 180 age and sex matched controls. Thirty-six appendices showed histologic signs of CD (40%): A transmural inflammation was found in 24 cases (67%), and a mucosal inflammation in 12 cases (33%). Histologic hallmarks of mucosal involvement were focal or discontinuous inflammation with crypt distortion and a histiocytic and lymphocytic predominant inflammation. Furthermore, epitheloid granulomas and erosions or ulcers with abundant histiocytes at the lesions base were observed. In comparison to controls luminal obliteration was significantly overrepresented in CD whereas acute phlegmonous appendicitis was underrepresented ( P<0.01). Patients with CD of the appendix showed a more widespread colonic involvement than those without ( P<0.01). This study shows that CD of the appendix exhibits specific histologic features that allow a differentiation from non-CD-associated appendicitis. CD-associated appendicitis is a frequent event, probably signifying a more widespread colonic involvement.