Although numerous reports describe the results of off-pump coronary artery bypass grafting (CABG) at specialized centers and in select patient populations, it remains unclear how off-pump CABG affects real-world patient outcomes. We conducted a large, multicenter observational cohort study of perioperative death and morbidity in on-pump (ON) versus off-pump (OFF) CABG. We reviewed Veterans Affairs Surgical Quality Improvement Program data for all patients (N=65,097) who underwent isolated CABG from October 1997 through April 2011 (intention-to-treat data were available from 2005 onward). The primary outcome was perioperative (30-day or in-hospital) death; the secondary outcomes were perioperative stroke, dialysis dependence, reoperation for bleeding, mechanical circulatory support, myocardial infarction, ventilator support ≥48 hr, and mediastinitis. Propensity scores calculated from age, 17 preoperative risk factors, and year of surgery were used to match 8,911 OFF with 26,733 ON patients. In the complete cohort, compared with the ON patients (n=53,468), the OFF patients (n=11,629) had less perioperative death (2.02% vs 2.53%, P=0.0012) and lower incidences of all morbidities except perioperative myocardial infarction. In the matched cohort, perioperative death did not differ significantly between OFF and ON patients (1.94% vs 2.28%, P=0.06), but the OFF group had lower incidences of all morbidities except for perioperative myocardial infarction and mediastinitis. A subgroup intention-to-treat analysis yielded similar but smaller outcome differences between the ON and OFF groups. Off-pump CABG might be associated with decreased operative morbidity but did not affect operative death, compared with on-pump CABG. Future studies should examine the effect of off-pump CABG on long-term outcomes. © 2014 by the Texas Heart ® Institute, Houston.