Objective Left main coronary artery disease (LMD) is a known risk factor for perioperative complications. This study compares off-pump coronary artery bypass (OPCAB) versus on-pump coronary artery bypass (ONCAB) grafting, CABG, with respect to in-hospital death, stroke, myocardial infarction, and major adverse cardiac events (MACE) in CABG patients with and without LMD. Methods Among 13,108 consecutive isolated patients with CABG treated from 1997 to 2007, 2891 patients (22.1%) were preoperatively found to have LMD. Of 5917 patients with OPCAB, 1276 (21.6%) had LMD, whereas among patients with ONCAB, 1615 of 7191 (22.5%) had LMD. Surgery type, LMD, and their interaction were examined for their impact on operative mortality, stroke, myocardial infarction, and MACE via multiple logistic regression models and adjusted odds ratios (AOR). Results Utilization of OPCAB for coronary revascularization in patients with LMD disease gradually increased from an initial low of 1.3% of patients in 1997 to a peak of 80.8% in 2007. OPCAB was associated with reduced incidence of stroke (AOR = 0.51, P < 0.001) and MACE (AOR = 0.66, P = 0.002), whereas LMD was associated with an increased incidence of MACE (AOR = 1.24, P = 0.038). No interactions between surgery type and LMD existed, meaning that the 2 conditions did not combine in any way to modify outcomes. Conclusions Patients with LMD are more likely to suffer a MACE event than those without LMD. Off-pump coronary artery bypass grafting is marginally associated with lesser risk of operative mortality and significantly associated with less stroke and overall MACE when compared with ONCAB. This benefit of OPCAB is similar for patients with and without LMD.