Three to 5 percent of the patients undergoing cardiac surgery are reoperated because of bleeding. When a surgical cause can be excluded, heparin/protamine mismatch may be considered. Insufficient reversal of heparin and overdosing of protamine may cause postoperative bleeding. The purpose of the study was to evaluate whether a heparin-protamine titration system, Hemochron RxDx, could reduce postoperative bleeding and blood transfusion. Fifty-three patients were included prospectively over a 6-month period. The test group (RxDx group; 28 patients) received heparin and protamine doses calculated using the Hemochron RxDx system, which performs a baseline activated clotting time (ACT) value together with a heparin response test. An accurate heparin dose was calculated based on the Bull dose/response curve. Protamine doses were calculated by the same method. In the control group (25 patients), heparin was administered based on weight (3.5 mg/kg) and monitored by ACT. Heparin was reversed with protamine (1 mg/l mg of total heparin). Postoperative bleeding was significantly lower in the RxDx group (375 mL; range, 125-700 mL) compared with the control group (600 mL; range, 250-1920 mL; p = .018). A reduced number of patients needed blood transfusions in the RxDx group, although this was not statistically significant (19% vs. 38%, respectively; p = .13). Initial heparin dose was significantly reduced in the RxDx group (250 mg; range, 100-375 mg) compared with the control group (300 mg; range, 200-350 mg; p = .04). The additional heparin during cardiopulmonary bypass (CPB) was significantly lower as well 62 (range, 0-185) vs. 100 mg (range, 0-350 mg); p = .04. Initial protamine dose was reduced in the RxDx group 200 (range, 75-340) vs. 350 mg (range, 200-500 mg); p = .0001. Satisfactory end ACT values were obtained in both groups. Using the Hemochron RxDx, we observed a significant reduction in postoperative blood loss, as well as the amount of heparin and initial doses of protamine used during CPB. Individual patient managed anticoagulation during cardiac surgery using dose/response curve techniques based on in vitro analysis of heparin and protamine seems to reduce bleeding.