BACKGROUND: The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) was investigated at a tertiary care hospital, and relationship was made between the clinical and genetic definitions of community- and healthcare-associated MRSA. METHODS: Nonduplicate isolates of S aureus were collected during 2004. Isolates were classified clinically as community-associated (CA) or healthcare-associated (HA). Molecular typing studies were performed on the isolates. RESULTS: Four hundred and two S aureus isolates were collected, of which 281 (70%) were MRSA. By clinical definition, 58 (21%) were classified as CA-MRSA and 215 (77%) as HA-MRSA. Among CA-MRSA, 36 (62%) harbored a SCCmec type IV gene. None of the SCCmec type IV CA-MRSA expressed inducible clindamycin resistance (MLSBi). Among 57 HA-MRSA isolates, 31 (54.4%) harbored a SCCmec type IV gene; MLSBi present in 5 (16%). Type IV SCCmec MRSA were most often associated with skin and soft tissue infections (RR 3.34 95% CI 1.43, 7.8). USA300 was the most common genotype among both CA- and HA-MRSA. CONCLUSIONS: Community-associated MRSA is a prominent pathogen with its most common genotype, USA300, representing a significant proportion of CA- and HA-MRSA infections in our institution. Clinical definitions of CA- and HA- status do not correlate well with the genetic definitions, particularly for HA-MRSA. © 2008 Southern Medical Association.