Virulence and mortality of Clostridium difficile-associated disease (CDAD) are increasing in the United States. Infant CDAD hospitalization incidence nearly doubled from 2.8 to 5.1 cases per 10,000 hospitalizations between 2000 and 2005. Because incidence of hospitalizations with other infectious enteritides has remained essentially stable, this growth in CDAD cannot be explained by a gastroenteritis reporting bias.