ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) strains are major pathogens causing infections of the skin and soft tissues and more serious, life-threatening diseases, including sepsis and necrotizing pneumonia. The vraSR operon encodes the key regulatory system that modulates the stress response of S. aureus elicited upon exposure to cell wall antibiotics. Mutation of vraS and vraR results in decreased oxacillin resistance in vitro . We investigated the effect of oxacillin treatment in experimental models employing a clinical USA300 MRSA strain (strain 923) and an isogenic vraSR deletion mutant (strain 923-M23). In a murine model of S. aureus necrotizing pneumonia, animals were treated with oxacillin, beginning 15 min after inoculation. Among mice infected with mutant strain 923-M23, oxacillin treatment significantly improved survival compared with saline treatment, whereas oxacillin treatment had no effect in mice infected with strain 923. Similarly, treatment with oxacillin decreased the bacterial burden among animals infected with strain 923-M23 but not among animals infected with strain 923. In a murine skin infection model, oxacillin eliminated the development of dermonecrosis among 923-M23-infected mice and decreased the bacterial burden in the lesions, but not among strain 923-infected mice. We conclude that deletion of the vraSR operon allowed an oxacillin regimen to be effective in murine models of MRSA pneumonia and skin infection. These findings provide proof-of-principle for development of a new antibiotic that could restore the usefulness of oxacillin against MRSA by inhibiting VraS or VraR.