Objective: Tirofiban (Aggrastat) is a reversible, nonpeptide inhibitor of platelet glycoprotein II/IIIa receptors. We tested the hypothesis that tirofiban preserves platelet number and function and shortens postoperative bleeding times in baboons after cardiopulmonary bypass. Methods: Four groups were studied: control, n = 12; low-dose tirofiban (0.1 μg/kg per minute), n = 7; high-dose tirofiban (0.3 μg/kg per minute), n = 7; and bolus tirofiban (15 μg/kg) followed by 0.1 μg/kg per minute during cardiopulmonary bypass, n = 7. After heparin, animals were perfused for 60 minutes at 50 ml/kg per minute and 37°C with a bubble oxygenator, roller pump, and peripheral cannulation. Hemodynamics, platelet count, platelet aggregation to adenosine diphosphate, and release of β-thromboglobulin were measured before tirofiban infusion, before heparin, after heparin before bypass, after 5 and 55 minutes of bypass, after protamine, and 60 minutes after protamine. Template bleeding times were measured at the same times except during cardiopulmonary bypass and 120 and 180 minutes after protamine administration. Platelet glycoprotein IIIa antigen was measured in Triton X-100 washes (Sigma Chemical Company) of the perfusion circuit after bypass. Results: High-dose tirofiban completely prevents platelet loss during cardiopulmonary bypass. β-Thromboglobulin release and sensitivity to adenosine diphosphate are significantly less than control at the end of bypass in all tirofiban groups. Template bleeding times return to preoperative values in both the low- and high-dose tirofiban groups 180 minutes after protamine administration and are significantly less than control bleeding times at both 120 and 180 minutes after protamine. Surface glycoprotein IIIa antigen does not significantly differ between groups. Conclusion: High-dose tirofiban completely preserves platelet number and improves platelet function during cardiopulmonary bypass in baboons and significantly accelerates restoration of normal template bleeding times after bypass.