A prospective cohort study of 399 consecutive patients in a single ward over an 11-month period was conducted to identify risk factors for nosocomial C. difficile colonization and diarrhea. The incidence of asymptomatic carriage was 13.0/100 patient admissions and the incidence of C. difficile-associated diarrhea was 7.8/100 patient admissions. Increased age and more severe underlying illness were associated with increased risk of C. difficile carriage and diarrhea. Multivariate models adjusting for age and severity of underlying disease associated two risk factors with asymptomatic C. difficile carriage: stool softeners (relative risk [RR] = 2.04) and antacids (RR = 1.80). Five risk factors were associated with C. difficile-associated diarrhea: cephalosporin use (RR = 2.07), penicillin use (RR = 3.41), enemas (RR = 3.26), gastrointestinal stimulants (RR = 3.06), and stool softeners (RR = 1.74). C. difficile was a common nosocomial infection on this ward, resulting in asymptomatic carriage more often than diarrhea and accounting for one-fifth of all cases of nosocomial diarrhea.