Rectal biopsy has a dual role in the diagnosis of infectious colitis. It can usually differentiate acute self-limited colitis (ASLC) from idiopathic inflammatory bowel disease (IBD), and it can also sometimes diagnose the specific infection in ASLC. Seven histologic features reliably differentiate IBD from ASLC: crypt distortion, crypt atrophy, a villous appearance of the surface epithelium, epithelioid granulomas, basally located isolated giant cells, basal lymphoid aggregates, and a lamina propria infiltrate of both acute and chronic inflammatory cells. One or more of these findings is frequent in rectal biopsies from patients with IBD, but rare in ASLC. Thus, the diagnosis of ASLC is made by the absence of the findings that characterize IBD. The usual histopathological picture of ASLC is nonspecific: normal architecture and increased numbers of acute inflammatory cells in the lamina propria. Certain findings may suggest a specific diagnosis. Granulomas may be present in specimens from homosexual men with proctitis due to C. trachomatis or T. pallidium. Granulomas are also present in schistosomiasis, tuberculosis, histoplasmosis, and yersinia enterocolitica infection. Typical viral inclusions can be seen in herpes simplex virus type II and cytomegalovirus infections. Specific parasites may be seen in biopsies from patients with amebiasis, schistosomiasis, and cryptosporidiosis. Intestinal spirochetosis is frequent in male homosexuals.