AIMS: We aimed to evaluate the efficacy of β-blockers after myocardial infarction (MI) across left ventricular ejection fraction (LVEF) strata and to assess the conclusiveness of the available evidence using trial sequential analysis (TSA). METHODS: PubMed, Embase and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) evaluating β-blockers in post-MI patients with LVEF ≥ 40%. A time-to-event meta-analysis was performed for the primary composite (as defined by each trial) and for individual endpoints. The Mantel-Haenszel method was used to pool risk ratios (RR) for major adverse cardiovascular events (MACE; death, MI or heart failure), including LVEF-stratified analyses. TSA estimated the required information size (RIS) and generated adjusted significance and futility boundaries, assuming a 5% type I error and 90% power. RESULTS: Across 19,826 post-MI patients (17,941 with LVEF ≥ 50% and 1885 with LVEF 40%-49%), β-blockers did not reduce time to the primary endpoint (HR 0.92, 95% CI 0.85-1.01; p = 0.08; I2 = 35%) or mortality. In patients with preserved LVEF (≥ 50%), β-blocker therapy did not reduce the risk of death or MACE (RR 0.96, 95% CI 0.87-1.05; I2 = 42%), with TSA confirming futility. Among those with mildly reduced LVEF (40%-49%), β-blockers reduced MACE (RR 0.74, 95% CI 0.58-0.94; I2 = 0%), although TSA failed to establish conclusiveness (RIS of 5717 [14.4%]). A significant interaction by LVEF subgroup was observed for cardiac death (p = 0.03). CONCLUSIONS: β-blockers conferred no benefit in post-MI patients with preserved LVEF, with conclusive evidence of futility, whereas therapy was associated with reduced MACE in those with mildly reduced LVEF, pending confirmation in further adequately powered randomized trials.