Prospective cohort study with medical record review. To evaluate the clinical utility of an infection control program in a patient cohort at high risk for methicillin-resistant Staphylococcus aureus (MRSA) infection and to identify risk factors interfering with successful decolonization of MRSA. All spinal cord injured (SCI) patients hospitalized at the Swiss Paraplegic Center (SPC) Nottwil from April 1991 to April 2001. Patients whose medical records indicated laboratory-confirmed MRSA colonization or infection were included. Incidence of MRSA colonization or infection was classified as community acquired, nosocomial or transferred based on standardized criteria. Risk factors for community-acquired MRSA colonization in SCI patients were determined. MRSA subtyping and identification of nosocomial spread was performed through pulse-field gel electrophoresis (PFGE). Of 5992 admissions, 100 episodes of MRSA (colonization 22 cases, infection 78 cases) were identified among 76 patients. Overall incidence (1991-2001) per 1000 patient days was 0.26 cases on admission compared to 0.08 at discharge (P<0.001). Community-acquired MRSA was most frequent (56%) followed by nosocomial acquisition (34%). PFGE subtyping identified two nosocomial clusters with six and three cases, respectively. Most of community-acquired MRSA isolates were genetically unrelated and also distinct from epidemic strains identified in Switzerland during the study period. Decolonization was successful in 60 of 76 (78.9%) MRSA-positive patients. In the largest European SCI center, MRSA controlling is feasible if infection control policies are vigorously applied.