Methicillin-resistant Staphylococcus aureus (MRSA) infection has emerged in patients who do not have the established risk factors. The national burden and clinical effect of this novel presentation of MRSA disease are unclear. We evaluated MRSA infections in patients identified from population-based surveillance in Baltimore and Atlanta and from hospital-laboratory-based sentinel surveillance of 12 hospitals in Minnesota. Information was obtained by interviewing patients and by reviewing their medical records. Infections were classified as community-associated [correction] MRSA disease if no established risk factors were identified. From 2001 through 2002, 1647 cases of community-associated [correction] MRSA infection were reported, representing between 8 and 20 percent of all MRSA isolates. The annual disease incidence varied according to site (25.7 cases per 100,000 population in Atlanta vs. 18.0 per 100,000 in Baltimore) and was significantly higher among persons less than two years old than among those who were two years of age or older (relative risk, 1.51; 95 percent confidence interval, 1.19 to 1.92) and among blacks than among whites in Atlanta (age-adjusted relative risk, 2.74; 95 percent confidence interval, 2.44 to 3.07). Six percent of cases were invasive, and 77 percent involved skin and soft tissue. The infecting strain of MRSA was often (73 percent) resistant to prescribed antimicrobial agents. Among patients with skin or soft-tissue infections, therapy to which the infecting strain was resistant did not appear to be associated with adverse patient-reported outcomes. Overall, 23 percent of patients were hospitalized for the MRSA infection. Community-associated MRSA infections are now a common and serious problem. These infections usually involve the skin, especially among children, and hospitalization is common. Copyright 2005 Massachusetts Medical Society.