A retrospective blind evaluation of rectal biopsy specimens from 44 patients with acute self-limited colitis and 104 patients with idiopathic inflammatory bowel disease was done. Seven histologic features proved highly discriminant because they occurred often in idiopathic inflammatory bowel disease but rarely, if at all, in acute self-limited colitis. The features with a high predictive probability (87%-100%) of diagnosing idiopathic inflammatory bowel disease were distorted crypt architecture, increased numbers of both round cells and neutrophils in the lamina propria, a villous surface, epithelioid granuloma, crypt atrophy, basal lymphoid aggregates, and basally located isolated giant cells. One or more of these features was present in 79% of all idiopathic inflammatory bowel disease cases. They were seen in both acute and chronic idiopathic inflammatory bowel disease. The biopsy features favoring acute self-limited colitis were less useful. Biopsy diagnosis of acute self-limited colitis is thus primarily based on the absence of histologic criteria favoring idiopathic inflammatory bowel disease. This study provides objective validation of histologic criteria in rectal biopsy that help differentiate acute self-limited colitis from idiopathic inflammatory bowel disease.