Confident monitoring of heparin during cardiopulmonary bypass and subsequent neutralization by protamine has been hampered by the absence of an accurate, reproducible, rapid, simple, and specific assay for heparin. By using two new instruments in tandem, one of which produced 0.5 ml of plasma in 1 min and one which specifically measures heparin in 3-4 min, heparin levels are available in approximately 5 min. By performing heparin assays at a variety of intervals, it was demonstrated that 76% of patients receiving common doses of heparin during cardiopulmonary bypass may have plasma levels that are potentially too low. Minimum neutralizing doses of protamine may be calculated using the formula: (estimated blood volume + pump prime volume) X (plasma heparin level/100) X 1.1 + 50. These doses were nearly two-thirds of previous doses and were unassociated with increased bleeding, clotting, or clinically significant heparin rebound.