Beta-blockers (BB) have been traditionally associated with improvement in cardiovascular disease outcomes in patients with ischemic cardiomyopathy. Whether they're still efficacious in the post-reperfusion era is currently debated in the light of recent controversial reports. In-hospital, 6-month and 12-month mortality were studied in the GULF-COAST, a prospective multicenter cohort of acute coronary syndrome (ACS), in relation to BB use: prior to admission, 24-hour post-admission and on discharge in patients with a left ventricular ejection fraction (LVEF) ≥ 40%. On admission, 50.9% of the cohort participants had a LVEF ≥ 40%, of whom 1203 (55.4%) were on BB whilst 905 (44.6%) were not. Mean age was 60 (13) years old and 66% were males. Prior BB use or its administration in 24 hours decreased in-hospital mortality (OR = 0.25, 95% CI [0.09-0.67]; OR = 0.16, 95% CI [0.08-0.35]; respectively). BB on discharge lowered 1-month mortality (OR = 0.28, 95% CI [0.11-0.72]), but had a neutral effect on mortality, reinfarction and stroke at 6 and 12 months. Results were unchanged after multivariable adjustments and further sensitivity analysis. In this retrospective cohort of ACS, BB improved in-hospital and 1-month mortality in patients with a LVEF ≥ 40% but had a neutral effect on longer-term outcome.