The effect of protamine sulfate on several cardiovascular and biochemical variables was studied in man under clinical conditions. This study was performed to quantitate these effects in 15 adult patients who had undergone cardiopulmonary bypass for coronary artery bypass grafting. Protamine was administered in typical clinical doses (3 mg/kg) at typical clinical rates (total dose infused over 5 minutes). This infusion rate is greatly in excess of the 50 mg/10 min suggested in the protamine package insert. No statistically significant changes in mean arterial blood pressure, cardiac output, central venous pressure, total or ionized calcium, PaO2, PaCO2, pH, Na+, or K+ were found during or after administration of protamine sulfate. Hypotension was observed after administration of protamine to one patient, but no etiologic mechanism was apparent. Previous reports suggest cardiovascular depression by protamine in the dog, a species highly susceptible to these effects. Data obtained in man in this study do not corroborate the canine studies.