Clumping factor A (ClfA) is a fibrinogen-binding cell wall-attached protein and an important virulence factor of Staphylococcus aureus. Previous studies reported that an immunization with the fibrinogen-binding domain of ClfA (ClfA(40-559)) protected animals against S. aureus infection. It was reported that some cytokines are involved in the pathogenesis of staphylococcal diseases and in host defense against S. aureus infection. However, the role of cytokines in the protective effect of ClfA(40-559) as a vaccine has not been elucidated. In this study, we demonstrated that the spleen cells of ClfA(40-559)-immunized mice produced a large amount of interleukin-17A (IL-17A). The protective effect of immunization was exerted in wild-type mice but not in IL-17A-deficient mice. IL-17A mRNA expression was increased in the spleens and kidneys of immunized mice after infection. CXCL2 and CCL2 mRNA expression was increased in the spleens and kidneys, respectively. Consistent with upregulation of the mRNA expression, neutrophils infiltrated into the spleens extensively and macrophage infiltration was observed in the kidneys of immunized mice. These results suggest that immunization with ClfA(40-559) induces the IL-17A-producing cells and that IL-17-mediated cellular immunity is involved in the protective effect induced by immunization with ClfA(40-559) against S. aureus infection.