Background Efficacy data on drug-eluting stents (DES) versus bare-metal stents (BMS) in saphenous vein grafts are controversial. We aimed to compare DES with BMS among patients undergoing saphenous vein grafts intervention regarding long-term outcome. Methods and Results In this multinational trial, patients were randomized to paclitaxel-eluting or BMS. The primary end point was major adverse cardiac events (cardiac death, nonfatal myocardial infarction, and target-vessel revascularization at 1 year. Secondary end points included major adverse cardiac events and its individual components at 5-year follow-up. One hundred seventy-three patients were included in the trial (89 DES versus 84 BMS). One-year major adverse cardiac event rates were lower in DES compared with BMS (2.2% versus 16.0%, hazard ratio, 0.14; 95% CI, 0.03-0.64, P=0.01), which was mainly driven by a reduction of subsequent myocardial infarctions and need for target-vessel revascularization. Five-year major adverse cardiac event rates remained lower in the DES compared with the BMS arm (35.5% versus 56.1%, hazard ratio, 0.40; 95% CI, 0.23-0.68, P<0.001). A landmark-analysis from 1 to 5 years revealed a persistent benefit of DES over BMS (hazard ratio, 0.33; 95% CI, 0.13-0.74, P=0.007) in terms of target-vessel revascularization. More patients in the BMS group underwent multiple target-vessel revascularization procedures throughout the study period compared with the DES group (DES 1.1% [n=1] versus BMS 9.5% [n=8], P=0.013). Enrollment was stopped before the target sample size of 240 patients was reached. Conclusions In this randomized controlled trial with prospective long-term follow-up of up to 5 years, DES showed a better efficacy than BMS with sustained benefits over time. DES may be the preferred strategy in this patient population. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00595647.