Methicillin‐resistant Staphylococcus aureus (MRSA) remains a major problem in hospitals, and it is now spreading in the community. A single toxin, Panton‐Valentine leukocidin (PVL), has been linked by epidemiological studies to community‐associated MRSA (CA‐MRSA) disease. However, the role that PVL plays in the pathogenesis of CA‐MRSA has not been tested directly. To that end, we used mouse infection models to compare the virulence of PVL‐positive with that of PVL‐negative CA‐MRSA representing the leading disease‐causing strains. Unexpectedly, strains lacking PVL were as virulent in mouse sepsis and abscess models as those containing the leukotoxin. Isogenic PVL‐negative (lukS/F‐PV knockout) strains of USA300 and USA400 were as lethal as wild‐type strains in a sepsis model, and they caused comparable skin disease. Moreover, lysis of human neutrophils and pathogen survival after phagocytosis were similar between wild‐type and mutant strains. Although the toxin may be a highly linked epidemiological marker for CA‐MRSA strains, we conclude that PVL is not the major virulence determinant of CA‐MRSA.