Adhesins are considered the most important virulence factors during early phases Staphylococcus aureus infection. Antibodies induced by vaccination toward an adhesin should reduce the adherence of the pathogen and augment its phagocytosis. The present report describes the immune response of mice to a DNA vaccine directed against one of these adhesins, clumping factor A (ClfA). Injection of plasmids expressing the fibrinogen-binding region A of ClfA induced a strong and specific antibody response to ClfA in mice. In addition, splenocyte proliferation was provoked by in vitro stimulation with recombinant ClfA, thus, indicating direct implication of these cells in the immune response. Pre-incubation of S. aureus with sera of vaccinated mice reduced the pathogen's ability to bind fibrinogen by up to 92%. These pre-incubated bacteria were phagocytosed by macrophages at an increased level in vitro and were less virulent in vivo in a mouse mastitis model. However, DNA-immunized mice were not protected against an intraperitoneal challenge. Overall, the results suggest that DNA immunization against adhesins represents a new and valuable approach to combat S. aureus infections.