Abstract The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) is changing. We determined the inhibitory and bactericidal activity of select antimicrobial agents utilizing a well-characterized group of 200 staphylococcal cassette chromosome mec (SCC mec) type IV community-associated MRSA (CAMRSA) and 50 SCC mec type II health care-associated MRSA (HAMRSA). Differences in carriage of the Panton-Valentine leukocidin (PVL) genes, agr group, and agr function in CAMRSA and HAMRSA were also examined. Pulsed-field gel electrophoresis (PFGE) patterns were determined for a subset of study strains. CAMRSA typically belonged to the USA 300 PFGE profile, were associated with high rates of PVL carriage (78%), and primarily were agr group I. Susceptibility to daptomycin, linezolid, teicoplanin, and vancomycin was 100%. In contrast, HAMRSA isolates typically belonged to the USA 100 PFGE profile, were associated with low rates of PVL carriage (8%), and primarily were agr group II. Comparing susceptibilities between the 2 types of MRSA strains, there was a 2-fold increase in MIC for daptomycin, doxycycline, teicoplanin, trimethoprim–sulfamethoxazole (TMP/SMX), and vancomycin in HAMRSA versus CAMRSA. Levofloxacin and clindamycin susceptibly decreased dramatically by 66% and 54%, respectively, against HAMRSA versus CAMRSA. With respect to agr function, 3.5% of CAMRSA and 48% of HAMRSA displayed a down-regulated agr gene cluster. The comparative bactericidal activities of daptomycin were similar to those of vancomycin and clindamycin, but were significantly greater than those of linezolid, teicoplanin, and TMP/SMX against CAMRSA at 24-h terminal end points. Further studies are warranted against a larger number of molecularly defined, geographically diverse CAMRSA to confirm these findings.