Background Hybrid coronary revascularization (HCR) combines minimally invasive left internal mammary artery to left anterior descending bypass with percutaneous coronary intervention of non-left anterior descending vessels. Its safety and effectiveness compared with conventional CABG have been under studied. Study Design Patients with multivessel disease and/or left main disease who underwent HCR at a US academic center between October 2003 and September 2013 were included. These patients were matched 1:3 to patients treated with CABG using a propensity-score matching algorithm. Conditional logistic regression and Cox regression analyses stratified on matched pairs were performed to evaluate the adjusted association between HCR and short- and long-term outcomes. Results The 30-day composite of death, MI, or stroke after HCR and CABG was 3.3% and 3.1% (odds ratio = 1.07; 95% CI, 0.52-2.21; p = 0.85) in the matched cohort of 1,224 patients (HCR, n =306; CABG, n = 918). Hybrid coronary revascularization was associated with lower rates of in-hospital major morbidity (8.5% vs 15.5%; p = 0.005), lower blood transfusion use (21.6% vs 46.6%; p < 0.001), lower chest tube drainage (690 mL; 25th to 75th percentile: 485 to 1,050 mL vs 920 mL, 25th to 75th percentile: 710 to 1,230 mL; p < 0.001), and shorter postoperative length of stay (<5-day stay: 52.6% vs 38.1%; p = 0.001). During a 3-year follow-up period, mortality was similar after HCR and CABG (8.8% vs 10.2%; hazard ratio = 0.91; 95% CI, 0.55-1.52; p = 0.72). Subgroup analyses in patients stratified by 2-vessel, 3-vessel, left main disease, and by Society of Thoracic Surgeons risk scores rendered similar results. Conclusions The use of HCR appeared to be safe, with faster recovery and similar outcomes when compared with conventional CABG. These findings were consistent irrespective of anatomic or predicted procedural risk.