Objectives: To evaluate the trend in Clostridium difficile infection (CDI) among hospitalized children in the United States and to evaluate the severity of and risk factors associated with these cases of CDI. Design: A retrospective cohort study using the triennial Healthcare Cost and Utilization Project Kids' Inpatient Database for the years 1997, 2000, 2003, and 2006. Setting: Hospitalized children in the United States. Participants: A nationally weighted number of patients (10 474 454) discharged from the hospital, 21 274 of whom had CDI. Main Exposure: Discharge diagnosis of CDI. Main Outcome Measures: Trend in cases of CDI; effect and severity were measured by length of hospital stay, hospitalization charges, colectomy rate, and death rate. Results: There was an increasing trend in cases of CDI, from 3565 cases in 1997 to 7779 cases in 2006 (P<.001). Patients with CDI had an increased risk of death (adjusted odds ratio [OR], 1.20; 95% confidence interval [95% CI], 1.01-1.43), colectomy (adjusted OR, 1.36; 95% CI, 1.04-1.79), a longer length of hospital stay (adjusted OR, 4.34; 95% CI, 3.97-4.83), and higher hospitalization charges (adjusted OR, 2.12; 95% CI, 1.98-2.26). There was no trend in death, colectomy, length of hospital stay, or hospitalization charges during the 4 time periods (ie, 1997, 2000, 2003, and 2006). The risk of comorbid diagnoses associated with CDI included inflammatory bowel disease, with an OR of 11.42 (95% CI, 10.16-12.83), and other comorbid diagnoses associated with immunosuppression or antibiotic administration. Conclusions: There is an increasing trend in CDI among hospitalized children, and this disease is having a significant effect on these children. In contrast to adults, there is no increasing trend in the severity of CDI in children. Children with medical conditions (including inflammatory bowel disease and immunosuppression) or conditions requiring antibiotic administration are at high risk of CDI. ©2011 American Medical Association. All rights reserved.