BACKGROUND Clostridium difficile infection (CDI) is increasingly recognized in patients with ulcerative colitis with ileal pouch-anal anastomosis (IPAA). The aim of this study was to identify clinical risk factors for treatment-refractory or recurrent CDI in patients with IPAA. METHODS We identified patients with IPAA for underlying ulcerative colitis and a positive polymerase chain reaction stool test for C. difficile at the Center for Ileal Pouch Disorders during the period from October 2010 to November 2013. Demographic clinical variables were compared between the refractory or recurrent CDI and nonrecurrent CDI groups. RESULTS Patients with IPAA with refractory or recurrent symptoms (refractory/recurrent CDI, the study group, N = 19) were compared with patients with a single antibiotic-responsive episode of ileal pouch CDI (nonrecurrent CDI, the control group, N = 21). The frequency of pouchitis before the index CDI was similar in the study and control groups (63.2% versus 66.7%, P = 0.82). Postoperative mechanical abnormalities occurred in 16 patients (84.2%) in the study group versus 7 patients (33.3%) in the control group (P = 0.0008). There were no differences between the two groups regarding hospitalization, non-C. difficile antibiotic use, the use of gastric acid-reducing therapy, or immunosuppressives before or after the index CDI. Six of 15 patients (40.0%) in the study group versus 1 of 15 patients (7.1%) in the control group had a low serum level of IgG1 (P = 0.031). CONCLUSIONS Refractory or recurrent disease is common in patients with ileal pouch with CDI. The presence of postsurgery mechanical intestinal complications or low serum immunoglobulin level may be risk factors for refractory or recurrent CDI in this patient population.