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Methicillin-resistant Staphylococcus aureus (MRSA) has traditionally been considered a health care–associated pathogen in patients with established risk factors. However, MRSA has emerged in patients without established risk factors (community-associated MRSA).To characterize epidemiological and microbiological characteristics of community-associated MRSA cases compared with health care–associated MRSA cases.Prospective cohort study of patients with MRSA infection identified at 12 Minnesota laboratory facilities from January 1 through December 31, 2000, comparing community-associated (median age, 23 years) with health care–associated (median age, 68 years) MRSA cases.Clinical infections associated with either community-associated or health care–associated MRSA, microbiological characteristics of the MRSA isolates including susceptibility testing, pulsed-field gel electrophoresis, and staphylococcal exotoxin gene testing.Of 1100 MRSA infections, 131 (12%) were community-associated and 937 (85%) were health care–associated; 32 (3%) could not be classified due to lack of information. Skin and soft tissue infections were more common among community-associated cases (75%) than among health care–associated cases (37%) (odds ratio [OR], 4.25; 95% confidence interval [CI], 2.97–5.90). Although community-associated MRSA isolates were more likely to be susceptible to 4 antimicrobial classes (adjusted OR, 2.44; 95% CI, 1.35–3.86), most community-associated infections were initially treated with antimicrobials to which the isolate was nonsusceptible. Community-associated isolates were also more likely to belong to 1 of 2 pulsed-field gel electrophoresis clonal groups in both univariate and multivariate analysis. Community-associated isolates typically possessed different exotoxin gene profiles (eg, Panton Valentine leukocidin genes) compared with health care–associated isolates.Community-associated and health care–associated MRSA cases differ demographically and clinically, and their respective isolates are microbiologically distinct. This suggests that most community-associated MRSA strains did not originate in health care settings, and that their microbiological features may have contributed to their emergence in the community. Clinicians should be aware that therapy with β-lactam antimicrobials can no longer be relied on as the sole empiric therapy for severely ill outpatients whose infections may be staphylococcal in origin.