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Objective.To review the effect of interventions, including a complete restriction in the use of fluoroquinolones (FQs), used to control an outbreak of hospital-onsetClostridium difficileinfection (HO-CDI) caused primarily by the epidemic North American pulsed-field gel electrophoresis type 1 strain.Design.Retrospective cohort and case-control study of all episodes of HO-CDI both before and after 2 interventions.Setting.Community hospital; January 1, 2005, through March 31, 2007.Interventions.Complete, 5-month, facility-wide restriction of fluoroquinolone use, during which a change in the environmental-services contractor occurred.Results.During a 27-month period, 319 episodes of HO-CDI occurred. The hospital-wide mean defined daily doses of antimicrobials decreased 22% after restricting FQ use, primarily because of a 66% decrease in the use of FQs. The interventions were also associated with a significant change in the HO-CDI incidence trends and with an absolute decrease of 22% in HO-CDI cases caused by the epidemic strain (from 66% before the intervention period to 44% during and after the intervention period;P= .02). Univariate analysis revealed that case patients with HO-CDI due to the epidemic strain were more likely than control patients, who did not have diarrhea, to receive a FQ, whereas case patients with HO-CDI due to a nonepidemic strain were not. However, FQ use was not significantly associated with HO-CDI in multivariable analysis.Conclusions.An outbreak of epidemic-strain HO-CDI was controlled at a community hospital after an overall decrease in antimicrobial use, primarily because of a restriction of FQ use and a change in environmental-services contractors. The restriction of FQ use may be useful as an adjunct control measure in a healthcare facilities during outbreaks of epidemic-strain HO-CDI.