This prospective study was designed to evaluate predictors of skin and soft tissue infections (SSTI) due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Consecutive patients who were hospitalized with S aureus SSTI were enrolled. CA-MRSA infection was diagnosed in 76% of the children. MRSA SSTI was associated with black race (P = .0001) and with infection involving the lower trunk (P = .008). Only 21% of the patients in this study had S aureus colonization in their nares, and in 3 cases there was discordance between the nares and the infection site cultures. Sensitivity, specificity, and predictive values of the risk factors examined were limited in their ability to predict CA-MRSA infection. Given the high prevalence of MRSA in our community and the inability of nasal cultures to reliably predict CA-MRSA infection, empirical antibiotic therapy active against CA-MRSA and contact isolation of patients are recommended.