BACKGROUND: Previous studies have found coronary artery bypass grafting (CABG) to be cost-effective compared with percutaneous coronary intervention (PCI) among patients with multivessel coronary artery disease (CAD), but their comparative effectiveness and economic outcomes may have changed. OBJECTIVES: This study sought to compare the economic and quality of life outcomes of CABG vs PCI and determine their cost-effectiveness in the FAME (Fractional Flow Reserve vs Angiography for Multivessel Evaluation) 3 randomized trial. METHODS: FAME 3 randomly assigned 1,500 patients with 3-vessel CAD to either CABG or fractional flow reserve-guided PCI using zotarolimus drug-eluting stents. We documented resource use and quality of life over 5 years of follow-up. We calculated costs by applying Medicare reimbursement rates to resources used, assessed quality of life using the EuroQOL EQ-5D, calculated quality-adjusted life-years (QALYs) from EQ-5D utility values, and used multivariable regression to compare outcomes by treatment assignment. We calculated the incremental cost-effectiveness ratio based on 5-year outcomes and also on projected life expectancies, and assessed its variability in 10,000 bootstrap replications. RESULTS: Cumulative costs over 5 years were 30% higher in patients assigned to CABG (95% CI: 16%-46%; P < 0.001). QALYs over 5 years did not differ significantly between the PCI (4.05 ± 0.84) and CABG groups (4.03 ± 0.82), although EQ-5D scores improved more rapidly after PCI. Patients <65 years of age at enrollment assigned to PCI were more likely to be employed at 5 years (56% vs 47%; P = 0.025). PCI had greater economic value than CABG over 5 years, with lower costs and higher QALYs in 66% of replications, and incremental cost-effectiveness ratios for CABG above the $150,000/QALY benchmark in 98% of bootstrap replications. These findings were essentially unchanged in several lifetime projections based on the outcomes documented within the trial follow-up period. CONCLUSIONS: Fractional flow reserve-guided PCI using zotarolimus drug-eluting stents provides significantly better long-term value than CABG for treatment of patients with multivessel CAD, with equivalent clinical outcomes at substantially lower cost.