OBJECTIVE: Recent changes in the epidemiology of Clostridium difficile infection include an increase in the incidence of C difficile-associated disease (CDAD) and the identification of patients with inflammatory bowel disease (IBD) as a group at risk. In addition, the effectiveness of antimicrobial therapies has been questioned. Our aim was to estimate the incidence of CDAD in a pediatric IBD population and review treatment efficacy. PATIENTS AND METHODS: We identified patients ages 18 years or younger from our center's IBD database who tested positive for C difficile toxin A and/or B between August 1, 2007 and December 31, 2008. Demographic information and treatment details were recorded. Chi-square and Fisher exact tests were used to compare categorical variables and the Student t test was used for continuous variables. RESULTS: From 372 pediatric patients with IBD, we identified 29 patients who experienced a total of 40 cases of CDAD. The annualized incidence rate of CDAD was 7.2%. Initial treatment was successful in 17 cases (43%). Eventual success was documented with metronidazole in 15 cases (41%), with vancomycin in 16 cases (43%), and with other agents or a combination of agents in 6 cases (16%). Age, sex, and IBD type were not associated with initial treatment outcome or recurrence. The choice of initial antimicrobial treatment was not associated with treatment outcome. The type of IBD therapy medication was not associated with the likelihood of CDAD recurrence, although the use of anti-inflammatory therapy was positively associated with initial antimicrobial treatment success. CONCLUSIONS: CDAD occurred frequently in our cohort of pediatric patients with IBD. Antimicrobial treatment success was achieved equally with either metronidazole or vancomycin. Initial treatment failed more than half of the time, regardless of medication choice. Apparent lack of antimicrobial efficacy in resolving symptoms may reflect resistant C difficile infection or increased IBD severity in a subset of patients who are C difficile carriers. Awareness of the potential for a high incidence of CDAD and frequent failure rate of initial therapy is important in the management of children with IBD. © 2011 Lippincott Williams & Wilkins, Inc.