Objective.To measure the effectiveness of an industrial systems-engineering approach to a methicillin-resistantStaphylococcus aureus(MRSA) prevention program.Design.Before-after intervention studySetting.An intensive care unit (ICU) and a surgical unit that was not an ICU in the Pittsburgh Veterans Administration hospitalPatients.Allpatientsadmittedtothe study unitsIntervention.We implemented an MRSA infection control program that consisted of the following 4 elements: (1) the use of standard precautions for all patient contact, with emphasis on hand hygiene; (2) the use of contact precautions for interactions with patients known to be infected or colonized with MRSA; (3) the use of active surveillance cultures to identify patients who were asymptomatically colonized with MRSA; and (4) use of an industrial systems-engineering approach, the Toyota Production System, to facilitate consistent and reliable adherence to the infection control program.Results.The rate of healthcare-associated MRSA infection in the surgical unit decreased from 1.56 infections per 1,000 patient-days in the 2 years before the intervention to 0.63 infections per 1,000 patient-days in the 4 years after the intervention (a 60% reduction;P= .003). The rate of healthcare-associated MRSA infection in the ICU decreased from 5.45 infections per 1,000 patient-days in the 2 years before to the intervention to 1.35 infections per 1,000 patient-days in the 3 years after the intervention (a 75% reduction;P= .001). The combined estimate for reduction in the incidence of infection after the intervention in the 2 units was 68% (95% confidence interval, 50%-79%;P< .001).Conclusions.Sustained reduction in the incidence of MRSA infection is possible in a setting where this pathogen is endemic. An industrial systems-engineering approach can be adapted to facilitate consistent and reliable adherence to MRSA infection prevention practices in healthcare facilities.