Background: Personalized prognosis plays a vital role in deciding between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with three-vessel disease (3VD). The aim of this study is to compare the modality of revascularization chosen by the local heart team to that recommended by using individualized predictions of medium, and long-term all-cause mortality amongst patients with 3VD screened in the Multivessel TALENT trial. Methods: The SYNTAX score II (SS-II) and SS-2020 were evaluated in 200 consecutive patients by a core laboratory and compared to the decision of the “on site” heart team. Results: According to the SS-II, CABG was the recommended treatment in 51 patients (25.5%) however 34 (66.6%) of them received PCI. According to SS-2020 the predicted absolute risk differences (ARD) between PCI and CABG were significantly higher in patients receiving CABG compared to those treated by PCI for major adverse cardiovascular and cerebrovascular events, a composite of all-cause mortality, stroke or myocardial infarction at 5-years (8.8 \pm 4.6% vs 6.0 \pm 4.0%, p 0.001) and all-cause mortality at 5- (5.2 \pm 3.5% vs 3.7 \pm 3.0%, p = 0.008) and 10-years (9.3 \pm 4.8% vs 6.2 \pm 4.2%, p 0.001). Based on the novel threshold of equipoise (individual absolute risk differences [ARD] 4.5%), 133 patients were eligible for PCI however 23 of them underwent CABG; conversely, amongst the 67 patients where CABG was recommendation (individual ARD >4.5%), only 19 received it. Conclusions: Despite the robustness of the risk models proposed for screening, several deviations from the recommended mode of revascularization were observed by the core laboratory among the first 200 patients with 3VD screened in the Multivessel TALENT trial. Clinical Trial Registration: ClinicalTrials.gov reference: NCT04390672.