The effects of rapid protamine administration via the left and right atria were compared. Preliminary studies first confirmed the safety of protamine administration via these routes, although decreases of up to 20 mm Hg were seen in the systolic blood pressure following protamine injection via the right atrium. Seventeen patients undergoing coronary artery bypass graft were studied, of whom nine received protamine via the right atrium and eight via the left atrium. Measurements of arterial pressure, left and right atrial pressure, cardiac output, and calculation of systemic vascular resistance and left ventricular stroke work index were made before and after protamine administration. Plasma histamine levels were measured in left atrial blood samples in 10 patients, before and after protamine injection. No significant change occurred after injection via the left atrial route, whereas a significant decrease in the systolic blood pressure and systemic vascular resistance with a transient increase in the cardiac index occurred after protamine administration via the right atrium. Plasma histamine levels were significantly higher after right atrial injection. It is concluded that histamine is released as protamine traverses the lungs following right atrial injection and produces peripheral vasodilation. Possible mechanisms for histamine release are discussed.