Abstract Aim The very long-term mortality of off-pump and on-pump CABG versus PCI in a randomized complex coronary artery disease (CAD) population is unknown. This study aims to investigate the impact of on-pump and off-pump coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) on 10-year all-cause mortality. Methods and results The SYNTAXES trial randomized 1800 patients with three-vessel and/or left main CAD to PCI or CABG and assessed their survival at 10 years. In this sub-study, the hazard of mortality over 10 years was compared according to the technique of revascularization: on-pump CABG (n=725), off-pump CABG (n=128), and PCI (n=903). There was substantial inter-site variation in the use of off-pump CABG despite baseline characteristics being largely homogeneous amongst the three groups. The crude rate of mortality was significantly lower following on-pump CABG versus PCI (25.6% vs 28.4%, Hazard Ratio [HR] 0.79, 95% Confidence Interval [CI] 0.65-0.96), whilst it was comparable between off-pump CABG and PCI (28.5% vs 28.4%, HR 0.98, 95%CI 0.69-1.40). After adjusting for the nine variables included in the SYNTAX score II 2020, 10-year mortality remained significantly lower with on-pump CABG than PCI (HR 0.75 against PCI, p=0.009) (central figure). Conclusion In the SYNTAXES trial, 10-year mortality adjusted for major confounders was significantly lower following on-pump CABG compared to PCI, whilst off-pump CABG offered no prognostic survival benefit over PCI. Site heterogeneity in the technique used in bypass surgery has had measurable effects on treatment performance. Given its impact on outcomes, it should be pre-stratified in future studies.Central figure