Background: It has been demonstrated that patients with three-vessel coronary artery disease respond better to coronary-artery bypass grafting (CABG) than to percutaneous coronary intervention (PCI). Aim of the Study: To compare the incidence of significant adverse cardiac or cerebrovascular events in patients with three-vessel coronary artery disease between fractional flow reserve (FFR) -guided PCI using current-generation drug-eluting stents and CABG. Patients and methods: One hundred patients with three-vessel coronary artery disease, identified angiographically and not involving the left main coronary artery, were included in this randomized prospective clinical study. This study comprised 100 patients who were randomly assigned into two groups: Group I: 50 patients underwent FFR-guided PCI. Group II: 50 patients underwent CABG. Results: The CABG group received an average of 3.7 distal anastomoses, with 34% receiving multiple arterial grafts and 92% receiving a left internal thoracic artery graft. The primary endpoint of MACCE was lower in the FFR-guided PCI group (6%) compared to the CABG group (10%). Secondary endpoints like death, spontaneous MI, stroke, and revascularization were generally higher in the CABG group, while target vessel revascularization was higher in the PCI group. Regarding safety, the PCI group had a significantly lower incidence of BARC type 3-5 bleeding (2% vs 16%) and atrial fibrillation (10% vs 28%) compared to CABG. Acute kidney injury and 30-day rehospitalization rates were insignificantly different between the groups. Conclusion: The FFR-guided PCI group had a lower incidence of MACCE at 6% compared to 10% in the CABG group.