Anticoagulation with unfractionated heparin has been the standard of care for more than a half-century for patients undergoing cardiac surgery. The risk of heparin-induced adverse reactions dictates the need for a safe and effective alternative, particularly in off-pump coronary artery bypass (OPCAB) surgery, an approach associated with a perioperative prothrombotic condition that may negatively influence graft patency. Between March 2003 and January 2005, 243 consecutive patients underwent OPCAB with bivalirudin (0.75 mg/kg bolus with 1.75 mg/kg per hour infusion). There were 171 men (70.4%) and 72 women (29.6%). The mean age was 64.9 +/- 10.9 years (age range 32-88 years). There were 147 patients (60.5%) with 3-vessel disease; 46 (18.9%) had substantial (>50%) stenosis of the left main coronary artery; 104 (42.8%) had a moderately reduced (0.30 to 0.50) ejection fraction; and 9 (3.7%) had a severely reduced (<0.30%) ejection fraction. Five patients (2.1%) required conversion to cardiopulmonary bypass and subsequently received heparin. Postoperative complications included perioperative myocardial infarction in 6 patients (2.5%), stroke in 3 (1.2%), prolonged ventilation in 4 (1.6%), reoperation for bleeding in 3 (1.2%), renal insufficiency in 14 (5.8%), atrial fibrillation in 26 (10.7%), low cardiac output in 3 (1.2%), and deep sternal infection in 1 (0.4%). Blood products were used in 117 patients (48.1%). The overall hospital mortality rate was 0.4% (1 of 243). Bivalirudin is a safe and effective anticoagulant that may be routinely used as an alternative to heparin and protamine in patients undergoing OPCAB. This is evidenced by low hospital mortality and morbidity rates. Further follow-up is warranted to discern the influence of bivalirudin on long-term clinical outcomes.