Hemorrhagic colitis is characterized by abdominal cramps, bloody diarrhea, and no or low-grade fever. Most cases are caused by the Shiga-like toxin-producing bacteria, Escherichia coli O157:H7. Nineteen colonic biopsy specimens and one resection specimen were reviewed from 11 patients with E. coli O157:H7-associated colitis to determine whether histologic features could be useful in diagnosis or in suggesting pathogenesis. All specimens showed hemorrhage and edema in the lamina propria. Specimens from nine patients were focally necrotic and showed hemorrhage and acute inflammation in the superficial mucosa with preservation of the deep crypts, similar to the pattern of injury associated with acute ischemic colitis. Specimens from five patients showed neutrophils focally infiltrating the lamina propria and crypts, resembling the pattern of injury seen in infectious colitis. One or both of these histologic patterns were observed in specimens from all but one patient. Specimens from four patients had poorly formed inflammatory pseudomembranes. It is concluded that the histologic features of E. coli O157:H7-associated colitis resemble a combination of ischemic and infectious injuries similar to those described in toxin-mediated Clostridium difficile-associated colitis. This suggests that the toxin(s) produced by these E. coliplay a role in the colonic injury. Infection with E. coli O157:H7 should be considered in the differential diagnosis of ischemic and infectious colitis.