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To evaluate the frequency, possible risk factors, and outcome of Clostridium difficile infection (CDI) in inflammatory bowel disease (IBD) patients.There has been an upsurge of CDI in patients with IBD who has been associated with increased morbidity and mortality. Various risk factors have been found to predispose IBD patients to CDI.A retrospective case–control study on IBD patients admitted with exacerbation and tested for CDI at the Tel Aviv Medical Center in 2008 to 2013. Epidemiologic, laboratory, and prognostic data were retrieved from electronic files and compared between patients who tested positive (CDI+) or negative (CDI−) for CDI.CDI was identified in 28 of 311 (7.31%) IBD patients hospitalized with diarrhea. IBD-specific risk factors (univariate analysis) for CDI included: use of systemic steroids therapy (odds ratio [OR] = 3.6, 95% confidence interval [CI] 1.2–10.6) and combinations of ≥2 immunomodulator medications (OR = 2.6, 95% CI 1.1–6.3). Additional risk factors for CDI that are common in the general population were hospitalization in the preceding 2 months (OR = 6.0, 95% CI 2.6–14.1), use of antacids (OR = 3.8, 95% CI 1.7–8.4), and high Charlson comorbidity score (OR = 2.5, 95% CI 1.1–5.7). A multivariate analysis confirmed that only hospitalization within the preceding 2 months and use of antacids were significant risk factors for CDI. The prognosis of CDI+ patients was similar to that of CDI− patients.Hospitalized IBD patients with exacerbation treated with antacids or recently hospitalized are at increased risk for CDI and should be tested and empirically treated until confirmation or exclusion of the infection.