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Acute self-limited colitis (ASLC) is a self-limiting diarrheal illness which is often caused by known infectious agents (Campylobacter, Salmonella, and Shigella), but many cases are of unknown etiology. This report describes the histopathologic features of acute self-limited colitis as related to its natural history. The extent of inflammation and regeneration varies with the duration of the disease. In the peak activity stage (within 0–4 days of onset of bloody diarrhea) there is mucosal edema, cryptitis, crypt ulcers, and abcesses. At the time of resolution (within 6–9 days of onset of bloody diarrhea), regenerative features become apparent along with residual focal neutrophilic cryptitis. In the later stages of resolution, along with some regenerative features, occasional crypts with transmigrating lymphocytes may be present.A rectal biopsy is diagnostic only in the early stages of the disease. Later in the course, the rectal biopsy from patients with ASLC may be nondiagnostic or may be confused with Crohn's disease due to the persistence of focal cryptitis. In our experience, the presence of crypt distortion and basal plasmacytosis are the two most useful criteria to differentiate chronic ulcerative colitis from ASLC.