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OBJECTIVES A hemostasis management system (HMS) is a point-of-care method for heparin and protamine titration. The authors hypothesized that protamine dosing over the HMS estimate would be associated with elevated activated clotting time (ACT), increased bleeding, and transfusion owing to protamine's anticoagulant activity. DESIGN A retrospective cohort study. SETTING Single-center university hospital. PARTICIPANTS One hundred eighty-nine patients undergoing elective coronary artery bypass grafting surgery. INTERVENTIONS Patients were stratified into 3 groups per ratio of actual total administered protamine versus the HMS-derived protamine estimate: (1) low-ratio (≤66% of HMS estimate), (2) moderate-ratio (66%-100% of HMS estimate), and (3) high-ratio (>100% of HMS estimate). MEASUREMENTS AND MAIN RESULTS The primary endpoints were post-protamine ACT, and residual heparin levels on HMS among the 3 groups in addition to bleeding and transfusion. There were 54 (28.6%) patients in the low, 95 (50.3%) in the moderate, and 40 (21.2%) in the high-ratio group. The high-ratio patients who were overdosed with protamine relative to the HMS estimate had elevated ACT, international normalized ratio, and activated partial thromboplastin time values, and subsequently received more red blood cell (RBC) and non-RBC transfusions compared to lower-ratio groups. Higher actual/HMS protamine ratios were associated independently with post-protamine ACT elevations after adjustment for sex, body mass index (BMI), and cardiopulmonary bypass (CPB) time. CONCLUSION Most patients received the protamine dose sufficiently close to the HMS estimate, but protamine dosing above the HMS estimate occurred in both obese and nonobese patients, which was associated independently with prolonged ACT after adjusting for sex, BMI, and CPB time.