PURPOSE: Ileal pouch-anal anastomosis is the surgical procedure of choice for selected patients with severe ulcerative colitis. Pouchitis is a common complication of this procedure, with most cases responding to treatment with metronidazole, possibly with the addition of 5-aminosalicylic acid drugs and steroids. Clostridium difficile can frequently colonize the colon after treatment with broad-spectrum antibiotics, giving rise to diarrhea or colitis. The aim of this report was to describe the first case of Clostridium difficile–associated diarrhea manifest as pouchitis. METHODS: The management of refractory pouchitis in a 35-year-old female with Clostridium difficile toxin in the stool is described followed by a literature review of small-intestinal Clostridium difficile infection. RESULTS: Assays for Clostridium difficile toxin on stool sent during an episode considered to be caused by idiopathic chronic pouchitis were positive, and treatment with oral vancomycin was initiated. The patient responded with a reduction in bowel frequency to twice daily, a successful discontinuation of her antidiarrheal medication, and a rapid increase in weight. A subsequent stool assay was negative for the toxin. CONCLUSIONS: Clostridium difficile infection can complicate pouchitis in patients with an ileal pouch-anal anastomosis and should be considered in patients who fail to respond to standard treatment, including metronidazole. In cases of refractory pouchitis, superadded infection with Clostridium difficile should be excluded before initiation of potent anti-inflammatory drugs.