Background: Since 1994 at the authors' institution, approximately 9000 cardiac surgical procedures were performed using activated clotting time (ACT)-monitored heparin anticoagulation for cardiopulmonary bypass and protamine administration calculated from a standard unchanged formula. This formula incorporates physiologic consequences of bypass pump-induced dilutional coagulopathy, platelet dysfunction, and coagulation/fibrinolytic cascade component activation, and thus may overcorrect in a subset of off-pump coronary artery bypass graft (OPCAB) patients who may in fact manifest a relative perioperative hypercoagulability state. This study evaluated a strategy of decreased protamine dosing in OPCAB. Methods: Eighty consecutive OPCAB patients who underwent surgery performed by a single surgeon at a single institution over a 12-month period were retrospectively analyzed. Patients underwent a mean of 2.91 ± 0.1 OPCAB grafts with full heparinization and 50% of the calculated protamine dose was administered. ACT, partial thromboplastin times, thoracostomy tube outputs, transfusions, and clinical outcomes were assessed. Results: Of 80 patients, 76 (95%) returned to baseline ACT values with 50% protamine dosing. All patients demonstrated intraoperative clinical evidence of hemostasis. Mean 8- and 24-hour thoracostomy tube outputs were 424 ± 24 mL and 806 ± 38 mL, respectively. A mean of 1.7 ± 0.2 packed red blood cell transfusions/patient was administered. There were no transfusions of platelets, fresh frozen plasma, or cryoprecipitate; no reexplorations; and no mortalities. Patients were discharged a mean of 4.4 ± 0.1 days postoperatively. Conclusion: A standard protamine dosing formula adequate for on-pump cardiac surgical procedures significantly overestimates protamine requirements for OPCAB. Patients treated with decreased protamine do not appear to have adverse outcomes.