Fibronectin binds specifically and irreversibly to Staphylococcus aureus. The expression of fibronectin-binding sites correlates with the invasivenessof the isolate. It has been suggested that the fibronectin receptor of S. aureus is either a protein or a carbohydrate that localizes at the surface of the bacterium, permitting interactions of the bacteria with the fibronectin of the host. Sites at which S. aureus typically initiates infection are rich in fibronectin, e.g., blood clots and subendothelium; the cells of the luminal surface of intact endothelium are among the few cell types that are relatively devoid of fibronectin. Removal of fibronectin receptors from S. aureus by mechanical means or by growing the bacteria in an antibiotic-containing medium decreases their ability to adhere. Thus, the fibronectin receptor appears to playa role in the initiation of S. aureus infections. These findings offer hope for the development of a vaccine that will prevent invasive disease - if the S. aureus fibronectin receptor(s) can be purified, proves to be immunogenic, and inhibits bacterial adherence to host tissues.