Systemic hypotension is commonly observed in association with the administration of protamine after cardiopulmonary bypass. Previous studies have not conclusively demonstrated whether protamine induces its effect by altering myocardial performance or by changing systemic vascular resistance (SVR) or both. To elucidate the hemodynamic effects of protamine sulfate administration (150 mg/m2 body surface area), we studied 22 patients following cardiopulmonary bypass. In Group I (N = 8) protamine was infused over 30 seconds and while in Group II (N = 8), over 60 seconds. Group III (N = 6) received calcium chloride (20 mg/kg) prior to protamine administration. The hemodynamic response was assessed by continuous recording of myocardial contractile element velocity (maximal value-Vpm), aortic blood flow, systemic and pulmonary arterial and right atrial pressures, and electrocardiogram. A significant (p less than 0.05) decrease in the systolic, diastolic and mean blood pressure was observed in all groups. A significant increase in cardiac index and a significant decrease in SVR was observed in all groups. A small depression in Vpm was detected in those patients who experienced a mean blood pressure fall greater than 10 mm Hh. Heart rate and left ventricular end-diastolic pressure (LVEDP) did not change significantly. The response to protamine sulfate among the three groups was similar. These results demonstrate that protamine-induced hypotension is primarily the result of peripheral vasodilatation only partically compensated by an increase in cardiac index. In some patients, these changes were associated with a small decline in myocardial contractile state. Hemodynamic changes were transient (less that 3 to 4 minutes), unrelated to the rate of administration, and not prevented by preinjection of calcium chloride.