Hemodynamic and hematologic responses to protamine sulfate reversal of heparin's anticoagulant effects were studied in 15 consecutive randomized patients undergoing aortic reconstructive surgery. In a double-blinded manner, patients were pretreated with either normal saline solution (n = 8) or protamine (0.75 mg/kg/3 min, n = 7)5 minutes before heparinization (150 IU/kg). After aortic grafts were placed, protamine (1.5 mg/kg/3 min) was administered intravenously to reverse the heparin. Arterial blood pressure, heart rate, pulmonary artery and capillary wedge pressure, central venous pressure, and cardiac output were monitored, as were platelet count, white blood cell count, activated clotting time, total hemolytic complement levels, and C3a levels. Calculated parameters included systemic vascular resistance and pulmonary vascular resistance. Pretreatment with protamine compared with saline solution prevented the hypotension (+6 vs. -16 mm Hg, p < 0.05) and declining pulmonary artery pressure (+ 1 vs. -7 mm Hg, p < 0.01) observed with protamine reversal of heparin. Significant differences between the two groups in central venous pressure and pulmonary vascular resistance were of less clinical relevance. Protamine pretreatment lessened the thrombocytopenia found during reversal compared with saline-pretreated patients although the difference was not statistically significant. Minimal hypotension occurring after protamine pretreatment alone was not accompanied by hemodynamic or hematologic changes, other than decreased heart rate. This study documents that low-dose protamine pretreatment attenuates the adverse effects of intravenously administered protamine used to reverse heparin anticoagulation in the clinical setting.