This study assessed the use of bivalirudin as an alternative anticoagulant in patients with heparin-induced thrombocytopenia-thrombotic syndrome (HIT/TS) or antiplatelet factor four-heparin (anti-PF4/H) antibodies undergoing off-pump coronary artery bypass (OPCAB). In a prospective, open-label, multicenter study, fifty-one patients with documented anti-PF4/H antibodies and (or) HIT/TS underwent OPCAB with bivalirudin anticoagulation (0.75 mg/kg i.v. bolus, 1.75 mg/kg/hour infusion). Procedural success (absence of death, Q-wave myocardial infarction, repeat revascularization, and stroke), bleeding, and transfusion at day seven/discharge, thirty days, and twelve weeks were assessed. Thirty-five patients (67%) were included with positive anti-PF4/H antibodies and no thrombocytopenia or thrombosis, eleven patients (22%) had thrombocytopenia, and five patients had clinical HIT/TS (10%). Procedural success at seven days/discharge was achieved in forty-seven patients (92%), while procedural success at thirty days and twelve weeks was 88%. There were no deaths. Chest tube output over the first twenty-four hours was 936 +/- 525 mL and twenty-five patients received a red blood cell transfusion during their hospitalization. Two patients required reexploration for persistent postoperative hemorrhage. Bivalirudin was an effective alternative anticoagulant for patients with HIT/TS or circulating anti-PF4/H antibodies undergoing OPCAB, with high rates of procedural success and an acceptable incidence of bleeding or transfusions.