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Outbreaks of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) have been noted in multiple sites in the United States. This study's purpose was to estimate trends in the incidence of and risk factors for clinically significant MRSA (CS-MRSA) infection in a cohort of HIV-infected adults.A retrospective clinic-based cohort (January 1, 2000-December 31, 2003) study.We ascertained all initial episodes of CS-MRSA and categorized them by primary site. Incidence rates were estimated by half year. Risk factors for CA-MRSA infection were identified using Cox modeling.Of 126 potential events, 94 were CS. Their primary sources were 83% skin or soft tissue, 10% blood, 6% respiratory, and 1.0% other sites. Among these, 60% were CA and 40% were nosocomial. Of antibiotics tested, only cotrimoxazole resistance was associated with nosocomial acquisition. The 3455 patients contributed 7003 person-years at risk. The incidence of CS-MRSA infection increased 6.2-fold from the first to the last half year. In multivariate analysis, independent predictors of CA-MRSA infection included HIV transmission by men who have sex with men or by injection drug use, CD4 count <50 cells/μL, log10 HIV plasma viral load, and absence of cotrimoxazole prophylaxis.The incidence of initial CS-MRSA events increased more than 6-fold in a 4-year period. The associations between CA-MRSA infection and HIV severity indicators merit examination in other cohorts.