Objectives: To evaluate the cost-effectiveness of alternative approaches to revascularization for patients with three-vessel or left main coronary artery disease (CAD). Background: Previous studies have demonstrated that, despite higher initial costs, long-term costs with bypass surgery (CABG) in multivessel CAD are similar to those for percutaneous coronary intervention (PCI). The impact of drug-eluting stents (DES) on these results is unknown. Methods: The SYNTAX trial randomized 1,800 patients with left main or three-vessel CAD to either CABG (n = 897) or PCI using paclitaxel-eluting stents (n = 903). Resource utilization data were collected prospectively for all patients, and cumulative 1-year costs were assessed from the perspective of the U.S. healthcare system. Results: Total costs for the initial hospitalization were 5,693/patienthigherwithCABG,whereasfollow−upcostswere2,282/patient higher with PCI due mainly to more frequent revascularization procedures and higher outpatient medication costs. Total 1-year costs were thus 3,590/patienthigherwithCABG,whilequality−adjustedlifeexpectancywasslightlyhigherwithPCI.AlthoughPCIwasaneconomicallydominantstrategyfortheoverallpopulation,cost−effectivenessvariedconsiderablyaccordingtoangiographiccomplexity.Forpatientswithhighangiographiccomplexity(SYNTAXscore>32),total1−yearcostsweresimilarforCABGandPCI,andtheincrementalcost−effectivenessratioforCABGwas43,486 per quality-adjusted life-year gained. Conclusions: Among patients with three-vessel or left main CAD, PCI is an economically attractive strategy over the first year for patients with low and moderate angiographic complexity, while CABG is favored among patients with high angiographic complexity