We evaluated the annual rate (cases/10,000 hospitalizations) of pediatric hospitalizations with Clostridium difficile infection (CDI; International Classification of Diseases, 9th revision, clinical modification code 008.45) in the United States. We performed a time-series analysis of data from the Kids' Inpatient Database within the Health Care Cost and Utilization Project during 1997-2006 and a cross-sectional analysis within the National Hospital Discharge Survey during 2006. The rate of pediatric CDI-related hospitalizations increased from 7.24 to 12.80 from 1997 through 2006; the lowest rate was for children <1 year of age. Although incidence was lowest for newborns (0.5), incidence for children <1 year of age who were not newborns (32.01) was similar to that for children 5-9 years of age (35.27), which in turn was second only to incidence for children 1-4 years of age (44.87). Pediatric CDI-related hospitalizations are increasing. A better understanding of the epidemiology and outcomes of CDI is urgently needed.