Background and Aims No-touch saphenous vein harvesting may enhance graft patency and improve clinical outcomes after coronary artery bypass grafting (CABG). Methods In this registry-based, randomized trial, patients undergoing CABG were randomly assigned to no-touch or conventional harvesting. The primary composite outcome was the proportion of patients with occluded/stenosed >50% vein graft on coronary computed tomography angiography, or who underwent percutaneous coronary intervention to a vein graft, or died. Secondary outcomes included clinical outcomes and leg wound complications. Results A total of 902 patients were enrolled with a mean total number of distal vein anastomoses of 2.0 (SD 0.87). The primary endpoint occurred in 90/454 (19.8%) of patients randomized to no-touch and in 107/446 (24.0%) of patients randomized to the conventional technique [difference, -4.3 percentage points; 95% confidence interval (CI) -10.1-1.6; P = .15] at a mean follow-up time of 3.5 (SD 0.1) years. The composite of death, myocardial infarction, or repeat revascularization at 4.4 (SD 1.3) years occurred in 57/454 (12.6%) and 44/446 (9.9%) in the no-touch and conventional groups, respectively (hazard ratio 1.3; 95% CI, 0.87-1.93). Leg wound complications were more common in patients assigned to no-touch harvesting at 3 months [107/433 (24.7%) vs. 59/427 (13.8%); difference, 10.9 percentage points; 95% CI 5.7-16.1]. At 2 years, 189/381 (49.6%) vs. 91/361 (25.2%) had remaining leg symptoms (difference, 24.4 percentage points; 95% CI 17.7-31.1). Conclusions No-touch vein graft harvesting for CABG was not superior to conventional open harvesting in reducing vein graft failure or clinical events after CABG but increased leg wound complications. The primary outcome requires cautious interpretation due to a lower-than-expected number of primary events.