A six-month outbreak of Clostridium difficile infection among elderly residents of a middle-term-care facility was investigated. Pulsed-field gel electrophoresis was used to genotype 22 outbreak strains and 30 epidemiologically unrelated strains. A prospective case-control study was conducted to identify risk factors for epidemic Clostridium difficile-associated diarrhea. All epidemiologically unrelated Clostridium difficile strains of the same serogroup could be differentiated by their DNA patterns with two restriction enzymes (SmaI and KspI). Among clustered strains, two epidemic serogroups (C and K) were identified. Two different DNA patterns were identified among serogroup C strains and three among serogroup K strains. Multivariate analysis showed that the risk of Clostridium difficile infection increased with antimicrobial chemotherapy (beta-lactam agents and pristinamycin) and the presence of a feeding tube. This study confirms the high discriminative power of restriction fragment length polymorphism analysis by pulsed-field gel electrophoresis to describe Clostridium difficile epidemiology. The typing results confirm that infection was principally exogenous in this outbreak. Furthermore, they indicate the need to improve all measures limiting transmission of infection.