Acute self-limited colitis (ASLC) must be distinguished from chronic ulcerative colitis (CUC) for the proper early management of patients with the acute onset of bloody diarrhea. This study was undertaken to determine if any clinical, endoscopic, microbiologic, or histologic parameters can be used to make this distinction reliably and quickly. Forty-eight patients with ASLC, 36 patients with chronic ulcerative colitis during their first attack [CUC(F)], and 84 patients with recurrent flares of chronic ulcerative colitis [CUC(R)] were studied prospectively. The presence of fever (temperature greater than 100 degrees F), abdominal pain, or the time from onset of bloody diarrhea to presentation were not discriminatory. Overall clinical and endoscopic severity were identical among the three groups. Microbiologic studies identified an infectious agent in only 42% of patients with ASLC. Histopathologic features always distinguished patients with CUC from those with ASLC. No case of ASLC was misdiagnosed histologically as CUC or vice versa. Plasmacytosis in the lamina propria extending to the mucosal base and mucosal distortion were present in all cases of CUC(F) and CUC(R), but were absent in all cases of ASLC. The finding of focal cryptitis during the resolving phase of ASLC could be confused with similar lesions in biopsy specimens from patients with Crohn's disease and mandates clinical follow-up. Histopathology is thus the only reliable diagnostic tool for the rapid differentiation of ASLC from CUC. However, biopsy specimens are only diagnostic when obtained during the acute phase of illness; that is, usually within the first 4 days from the onset of symptoms.