BACKGROUND: Current society guidelines recommend physiological assessment of intermediate coronary lesions to guide revascularization. Data regarding revascularization guided by vessel fractional flow reserve (vFFR), derived from three-dimensional quantitative coronary angiography without the need for a pressure wire or hyperemic agent, as compared with pressure-wire-based fractional flow reserve (FFR), are lacking. METHODS: We conducted an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients with intermediate coronary-artery lesions (diameter stenosis of 30 to 80%) who presented with chronic or acute coronary syndromes were randomly assigned in a 1:1 ratio to undergo either vFFR-guided or FFR-guided revascularization of the intermediate coronary-artery lesions. The primary end point was a composite of death from any cause, any myocardial infarction, or any revascularization at 1 year. The noninferiority margin was 3.0 percentage points. RESULTS: The primary end point was assessed in 1116 patients in the vFFR group and 1095 in the FFR group. The mean age of the patients was 67 years, 24.3% were women, 18.7% presented with an acute coronary syndrome, and 26.6% had diabetes mellitus. At 1 year, a primary end-point event had occurred in 80 patients (Kaplan-Meier estimate, 7.5%) in the vFFR group and in 79 patients (Kaplan-Meier estimate, 7.5%) in the FFR group (risk difference, -0.02 percentage points; 95% confidence interval, -2.25 to 2.21; P = 0.004 for noninferiority). The incidence of serious adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with intermediate coronary lesions, vFFR-guided revascularization was noninferior to FFR-guided revascularization with respect to a composite of death, myocardial infarction, or revascularization at 1 year. (Funded by Pie Medical Imaging and Siemens Healthineers; FAST III ClinicalTrials.gov number, NCT04931771.).