Background: Hybrid coronary revascularization (HCR), which combines minimally invasive bypass surgery and percutaneous coronary intervention of non-LAD vessels, constitute a less invasive alternative to conventional coronary artery bypass grafting (CABG). The safety and effectiveness of HCR in acute coronary syndromes (ACS) as a surgical coronary revacularization strategy is unknown. Methods: Patients presenting with ACS who underwent HCR at a U.S. academic center (1/2008-9/2013) were included. These patients were matched 1:4 to similar individuals who underwent CABG using a propensity-score matching algorithm. Conditional logistic regression and Cox regression stratified on matched pairs were performed to evaluate the association of HCR versus CABG on the outcomes of 30-day MACCE (a composite of mortality, myocardial infarction (MI) and stroke), peri-procedural complications, and 3-year mortality. Results: Of 585 patients (HCR=117, CABG=468) in the propensity-score matched cohort, the 30-day MACCE was comparable after HCR and CABG (4.3% vs. 3.6%, odds ratio: 1.19, 95%-CI:0.43-3.19, p=0.75). Compared with CABG, HCR resulted in fewer procedural complications (7.7% vs. 16.0%, p=0.037), fewer blood transfusions (0 95%-CI:0-0 vs 1 95%-CI:0-2, p<0.001), lower chest-tube drainage (760cc 95%-CI:555-1090 vs. 890cc 95%-CI:660-1130, p<0.001) and shorter length-of-stay (4, 95%-CI:3-5 versus 5, 95%-CI:4-7 days, p<0.001). Over a 3-year follow-up period, mortality was similar after HCR and CABG (6.0% vs. 7.0%, hazard ratio: 0.92, 95%-CI:0.33-2.54, p=0.87). Conclusion: In this exploratory analysis we found that among patients with ACS the use of HCR appeared safe, with fewer procedural complications, less blood product use, and faster recovery with similar longitudinal outcomes relative to conventional CABG surgery. Future multi-center studies involving a large number of patients with ACS are needed to confirm these findings.