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A series of measures were implemented, in a secondary/tertiary-care hospital in Quebec, to control an epidemic of nosocomial Clostridium difficile-associated disease (n-CDAD) caused by a virulent strain; these measures included the development of a nonrestrictive antimicrobial stewardship program. Interrupted time-series analysis was used to evaluate the impact of these measures on n-CDAD incidence. From 2003–2004 to 2005–2006, total and targeted antibiotic consumption, respectively, decreased by 23% and 54%, and the incidence of n-CDAD decreased by 60%. No change in n-CDAD incidence was noted after strengthening of infection control procedures (P = .63), but implementation of the antimicrobial stewardship program was followed by a marked reduction in incidence (P = .007). This suggests that nonrestrictive measures to optimize antibiotic usage can yield exceptional results when …