We reviewed Clostridium difficile-associated disease (CDAD) data from the intensive care unit (ICU) and hospital-wide surveillance components of the National Nosocomial Infections Surveillance System hospitals during 1987-2001. ICU CDAD rates increased significantly only in hospitals with >500 beds (P<.01) and correlated with the duration of ICU stay (r=0.82; P<.05). Hospital-wide (non-ICU) rates increased only in hospitals with <250 beds (P<.01) and in general medicine patients versus surgery patients (P<.0001). CDAD predominated in general hospitals versus other facility types, and rates were significantly higher during winter versus nonwinter months (P<.01). Thus, prevention efforts should be targeted to high-risk groups in these settings.