This study evaluated the prevalence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) infections among patients with skin and soft-tissue infections in 11 U.S. cities. A total of 422 patients were enrolled, with 320 (76%) having S. aureus isolated from their infections. Of these, 249 (78%) were MRSA, with a prevalence of 59% overall. MRSA was the most common identifiable cause of skin and soft-tissue infections in 10 of the 11 emergency departments studied. Pulsed-field gel electrophoresis (PFGE) identified USA300 as the most common MRSA type, accounting for 97% of isolates. SCCmec type IV and the Panton-Valentine leukocidin (pvl) gene were present in 98% of MRSA isolates. Most MRSA isolates were susceptible to clindamycin, rifampin, and trimethoprim-sulfamethoxazole, but 57% of patients with MRSA infections received antibiotic therapy not concordant with susceptibility testing. Among methicillin-susceptible S. aureus (MSSA) isolates, 31% were USA300 and 42% contained pvl genes. MRSA was more common in patients with certain risk factors, such as a history of MRSA infection or recent hospitalization. The study highlights the increasing prevalence of community-associated MRSA and the need for clinicians to consider MRSA coverage when prescribing antibiotics for skin and soft-tissue infections. The findings suggest that empirical antibiotic therapy should be modified to account for MRSA prevalence, especially in areas with high community-associated MRSA rates. The study also emphasizes the importance of obtaining cultures and implementing infection control measures to prevent the spread of MRSA.This study evaluated the prevalence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA) infections among patients with skin and soft-tissue infections in 11 U.S. cities. A total of 422 patients were enrolled, with 320 (76%) having S. aureus isolated from their infections. Of these, 249 (78%) were MRSA, with a prevalence of 59% overall. MRSA was the most common identifiable cause of skin and soft-tissue infections in 10 of the 11 emergency departments studied. Pulsed-field gel electrophoresis (PFGE) identified USA300 as the most common MRSA type, accounting for 97% of isolates. SCCmec type IV and the Panton-Valentine leukocidin (pvl) gene were present in 98% of MRSA isolates. Most MRSA isolates were susceptible to clindamycin, rifampin, and trimethoprim-sulfamethoxazole, but 57% of patients with MRSA infections received antibiotic therapy not concordant with susceptibility testing. Among methicillin-susceptible S. aureus (MSSA) isolates, 31% were USA300 and 42% contained pvl genes. MRSA was more common in patients with certain risk factors, such as a history of MRSA infection or recent hospitalization. The study highlights the increasing prevalence of community-associated MRSA and the need for clinicians to consider MRSA coverage when prescribing antibiotics for skin and soft-tissue infections. The findings suggest that empirical antibiotic therapy should be modified to account for MRSA prevalence, especially in areas with high community-associated MRSA rates. The study also emphasizes the importance of obtaining cultures and implementing infection control measures to prevent the spread of MRSA.