Staphylococcal protein A (SpA), a cell wall anchored protein of Staphylococcus aureus, has the ability to interact with several host components, possibly indicating a role as a virulence factor in S. aureus infections. In this study, the contribution of SpA to bacterial virulence was investigated in a murine model of S. aureus arthritis. Intravenous inoculation of S. aureus wild-type strain Newman gave rise to more severe arthritis and higher mortality than the isogenic spa mutant strain DU5873. The wild-type strain caused more in vitro spleen cell proliferation than the SpA-deficient strain. However, IL-6 and TNF-alpha levels were higher after stimulation with thespa mutant strain compared to the wild-type strain. To conclude, our results clearly indicate that SpA is a virulence factor of S. aureus in murine septic arthritis.