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Clostridium difficile infection (CDI) in patients with the ileal pouch after proctocolectomy has been increasingly recognized. We sought to evaluate the frequency and risk factors of CDI in patients with the primary or secondary discharge diagnosis of pouchitis in the United States.We reviewed the National Inpatient Sample of the Healthcare Cost and Utilization Project and identified patients admitted for pouchitis with underlying inflammatory bowel disease (IBD) or familial adenomatous polyposis (FAP), between 2010 and 2012. Cases with CDI were identified based on a concomitant primary or secondary discharge diagnosis for CDI. The frequency of CDI was estimated in patients with underlying IBD and FAP. Multivariable analysis was conducted to study the risk factors associated with CDI in those with pouchitis with underlying IBD.A total of 3566 eligible patients with pouchitis were identified during the study period. Eighty-nine patients (2.5%) had CDI as a concomitant primary or secondary discharge diagnosis. CDI was identified in 2.6% (99.9% confidence interval [CI], 1.3–3.8) of pouchitis patients with underling IBD. None of the patients with pouchitis with underlying FAP were found to have CDI during the study period. Among pouchitis patients with underlying IBD, the presence of nonalcoholic fatty liver disease (odds ratio = 5.4; 95% CI, 1.5–19.9), obesity (odds ratio = 5.5; 95% CI, 1.4–21.4), or obstructive sleep apnea (odds ratio = 10.3; CI, 2.0–53.7) was associated with an increased risk of CDI.It seems that CDI was limited to pouchitis with underlying IBD and rare in those with underlying FAP. Patients with nonalcoholic fatty liver disease, obesity, and obstructive sleep apnea are at an increased risk of C. difficile pouchitis among patients with IBD.