Platelets adhering to artificial or biologic surfaces have been implicated in the pathogenesis of catheter infections or endocarditis; however, the ligands involved in Staphylococcus aureus interaction. with adherent platelets remain incompletely understood. Radiolabeled S. aureus Cowan 1 were incubated with purified platelets adherent to polymethylmethacrylate (PMMA) coverslips and washed, and adhesion was determined. Platelets promoted adhesion of S. aureus ∼30-fold compared with adhesion to albumin-PMMA. In the presence of both plasma (1% vol/vol) and platelets, adhesion was extensively promoted, with 30% (of inoculated) S. aureus adherent (150fold increase). Platelet pretreatment with anti-GPIIb/IIIa monoclonal antibodies or inhibitors of platelet activation decreased plasma-enhanced adhesion, suggesting a role of platelet activation in S. aureus adhesion. Plasma-enhanced adhesion was sensitive to thrombin antagonists, proteinase inhibitors, heparin, or antifibrinogen antibodies, indicating that fibrinogen/fibrin is necessary for bridging between adherent platelets and S. aureus. In conclusion, S. aureus adhesion to immobilized platelets may playa role in the pathogenesis of invasive bloodstream infections or endocarditis.