Background: In the United States, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as the predominant cause of skin infections. Trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin are often used as first-line treatment options, but clinical data are lacking.Methods: We conducted a retrospective cohort study of outpatients with skin and soft tissue infections managed from July 1 to December 31, 2006. Patients younger than 18 years of age were excluded, as were those who had no clinical admission or progress notes; were hospitalized within the 90 days before admission; were hospitalized with polymicrobial, surgical site, catheter-related, or diabetic foot infections; or were discharged to places other than home. Patient demographics, comorbidities, diagnoses, cultures, prescribed antibiotics, susceptibilities, surgical procedures, and health outcomes were extracted from electronic medical records. Patients were divided in 2 cohorts for further analysis: TMP-SMX and clindamycin. The primary study outcome was composite failure defined as an additional positive MRSA culture from any site 5 to 90 days after treatment initiation or an additional intervention during a subsequent outpatient or inpatient visit. Baseline characteristics and failure rates were compared using