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We investigated a large outbreak of community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections in southwestern Alaska to determine the extent of these infections and whether MRSA isolates were likely community acquired.Retrospective cohort study.Rural southwestern Alaska.All patients with a history of culture-confirmed S. aureus infection from March 1, 1999, through August 10, 2000.More than 80% of culture-confirmed S. aureus infections were methicillin resistant, and 84% of MRSA infections involved skin or soft tissue; invasive disease was rare. Most (77%) of the patients with MRSA skin infections had community-acquired MRSA (no hospitalization, surgery, dialysis, indwelling line or catheter, or admission to a long-term–care facility in the 12 months before infection). Patients with MRSA skin infections were more likely to have received a prescription for an antimicrobial agent in the 180 days before infection than were patients with methicillin-susceptible S. aureus skin infections.Our findings indicate that the epidemiology of MRSA in rural southwestern Alaska has changed and suggest that the emergence of community-onset MRSA in this region was not related to spread of a hospital organism. Treatment guidelines were developed recommending that beta-lactam antimicrobial agents not be used as a first-line therapy for suspected S. aureus infections.