Background. Cardiopulmonary bypass (CPB) has pathophysiologic sequelae that may be more severe in high-risk subsets. We wanted to determine whether off-pump coronary bypass (OPCAB) could optimize outcomes. Methods. Our database of 242 OPCAB patients undergoing complete revascularization was compared to a base of 483 CABG patients undergoing CPB. Results were compared for the overall series and in the following high-risk subsets: 80 years of age or older, ventricular dysfunction (ejection fraction (EF) less than or equal to 0.25), prior neurologic event or renal failure, chronic obstructive pulmonary disease (COPD), and reoperation. Results. In the overall series, OPCAB significantly reduced the incidence of intraoperative transfusion requirements and showed a trend toward reduced morbidity in terms of postoperative neurologic and renal complications, prolonged ventilator requirement greater than 3 days, and bleeding requiring reexploration. Mortality was less in the OPCAB group (0.4% versus 2.7%, p = not significant). Similar results were achieved in the following high-risk subgroups (n = off-pump/on-pump): 80 years of age or older (n = 28/58), EF less than or equal to 25% (n = 13/26), preoperative neurologic event (n = 25/36), preoperative renal failure (n = 27/46), COPD (n = 33/43), and reoperation (n = 28/76). OPCAB decreased the incidence of prolonged Ventilation in COPD patients (0/33 [0%] versus 4/43 [9.3%] p = not significant) and decreased the incidence of renal complications in the elderly (1/28 [3.6%] versus 9/58 [15.5%] p = not significant). Off-pump coronary bypass reduced but did not eliminate neurologic events in the elderly (2/28 [7.1%] versus 8/58 [13.8%] p = not significant). Conclusion: Off-pump coronary bypass significantly reduced the incidence of transfusion requirement compared to the CPB counterparts and had a consistent trend in reducing morbidity and mortality overall and in all high-risk subsets. Neurologic events are not eliminated in OPCAB. (Ann Thorac Surg 2000;70:1546-50) (C) 2000 by The Society of Thoracic Surgeons.