Abstract This study aimed to explore the validity of the use of the net clinical benefit (NCB), i.e. the sum of major bleeding and thrombotic events, as a potential surrogate for all-cause mortality in clinical trials assessing antithrombotics. Published randomized controlled trials testing anticoagulants in the prevention or treatment of venous thromboembolism (VTE) and non-valvular atrial fibrillation (NVAF) were systematically reviewed. The validity of NCB as a surrogate endpoint was estimated by calculating the strength of correlation of determination (R 2 ) and its 95% confidence interval (CI) between the relative risks of NCB and all-cause mortality. Amongst the 125 trials retrieved, the highest R 2 trial values were estimated for NVAF (R 2 trial = 0.41, 95% CI [0.03; 0.48]), and acute VTE (R 2 trial = 0.30, 95% CI [0.04; 0.84]). Conversely, the NCB did not correlate with all-cause mortality in prevention studies with medical (R 2 trial = 0.12, 95% CI [0.00; 0.36]), surgical (R 2 trial = 0.05, 95% CI [0.00; 0.23]), and cancer patients (R 2 trial = 0.006, 95% CI [0.00; 1.00]). A weak correlation between NCB and all cause-mortality was found in NVAF and acute VTE, whereas no correlation was observed in clinical situations where the mortality rate was low. Consequently, NCB should not be considered a surrogate outcome for all cause-mortality in anticoagulation trials.