Clostridium difficile-associated pseudomembranous colitis is an increasingly common nosocomial infection that usually responds to oral antibiotics. Presentation as an acute abdomen occurred in 12 patients, leading to 14 laparotomies. A distinctive clinical picture was observed: advanced age, recent treatment with antibiotics, fever, abdominal pain, tenderness, marked leukocytosis, and ileus. Only six of the 12 patients had diarrhea. Five were immunosuppressed. Abdominal computed tomographic scans revealed ascites and a massively thickened colonic wall. All four patients treated by subtotal colectomy survived. Four of 10 patients treated only with laparotomy or segmental colectomy died, four responded to medical therapy, and the conditions of two deteriorated but were salvaged by subtotal colectomy. Early diagnosis via endoscopy or computed tomography should obviate the need for exploratory operations. However, progressive toxic effects indicate failure of medical therapy and the need for subtotal colectomy.