BACKGROUND In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, patients with 3-vessel or left main coronary artery disease (CAD) had improved long-term outcomes with coronary artery bypass graft (CABG) surgery compared with percutaneous coronary intervention (PCI) with drug-eluting stents (DES), improvements driven mainly by differences in myocardial infarction and repeat revascularization. OBJECTIVES This study compared the long-term quality-of-life benefits of DES-PCI versus CABG for patients with 3-vessel or left main CAD. METHODS Between 2005 and 2007, the SYNTAX trial randomized 1,800 patients with 3-vessel or left main CAD to either CABG or DES-PCI. Health status was assessed at baseline and at 1, 6, 12, 36, and 60 months by using the Seattle Angina Questionnaire (SAQ) and the 36-Item Short Form Health Survey. RESULTS At 5-year follow-up, CABG was superior to DES-PCI on several SAQ domains including angina frequency and physical function, as well as the role physical and role emotional scales of the 36-Item Short Form Health Survey. Subgroup analysis demonstrated a significant interaction between angiographic complexity (as assessed by the SYNTAX score) and angina relief (mean difference in the SAQ angina frequency score for CABG vs. PCI of -0.9, 3.3, and 3.9 points for low, intermediate, and high SYNTAX score patients, respectively; p = 0.048 for interaction). CONCLUSIONS Among patients with 3-vessel or left main CAD, both CABG and DES-PCI were associated with substantial and sustained quality-of-life benefits over 5 years of follow-up. In general, CABG resulted in greater angina relief, although the absolute treatment benefit was small. Angina relief at 5 years was enhanced with CABG among patients with high SYNTAX scores, a finding reinforcing the recommendation that CABG should be strongly preferred for such patients. (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery [SYNTAX]; NCT00114972) (C) 2017 by the American College of Cardiology Foundation.