Adhesins are considered the most important virulence factors during early phase Staphylococcus aureus infection. The present report describes a newly fusion protein, named Cna-FnBP that was constructed by fusion of the fnb and cna genes of S. aureus and expressed in E. coli. The recombinant protein was designed to broaden the function spectrum of block binding activity to S. aureus adhesion. Vaccination of the recombinant protein induced a strong and specific humoral response to Cna-FnBP in mice. In addition, splenocyte proliferation was provoked by in vitro stimulation with recombinant Cna-FnBP, thus, indicating direct implication of these cells in the immune response. These pre-incubated bacteria were phagocytosed by neutrophils at an increased level in vitro in a mouse model. Mice immunized with Cna-FnBP survived significantly longer following the challenge with S. aureus than nonimmunized mice did. These results indicate that Cna-FnBP is a promising vaccine for the prevention of S. aureus infections. Overall, the results suggest that fusion compounds which elicted from ECM-binding proteins (ECMBPs) were used to immunize against adhesins represents a valuable approach to combat S. aureus infections.