The nematode Caenorhabditis elegans has recently been developed as a host model for the study of Staphylococcus aureus virulence and pathogenesis. Here, the toxicity and virulence of representative clinical isolates of our methicillin-resistant S. aureus (MRSA) epidemic strains were studied using this model. The strains USA300 (associated with community infection outbreaks), USA400 (associated with sporadic community infections) and CMRSA2 (associated with both hospital and community infections), as well as the nematocidal reference strain NCTC8325, showed high nematocidal activity, both by killing the majority of the nematodes (> 90%) over 9 days, and by inhibiting second-generation nematode growth. By contrast, the typical hospital-associated MRSA strain CMRSA6, the colonization strain M92, and the non-pathogenic Staphylococcus epidermidis control strain ATCC12228 were non-toxic to the nematode, which behaved normally. The absence of nematocidal activity does not reflect lack of growth or reduced growth of the bacterial inoculum. The two non-nematocidal strains share similar genomic backgrounds, bacterial growth curve patterns and virulence gene profiles. However, the nematocidal strains each showed the same low maximum density growth curve patterns, but possessed distinct genetic profiles; no common virulence gene patterns or specific genes have been elucidated. Our findings demonstrate that community-associated MRSA strains are more pathogenic than hospital-associated MRSA in the C. elegans model and support the use of this model for studying the virulence of S. aureus strains.