Abstract Aims This observational study aimed to investigate the association between beta-blocker therapy and clinical outcomes in patients with acute myocardial infarction (AMI), especially with mid-range or preserved left ventricular systolic function. Methods and results Among 13 624 patients enrolled in the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH), 12 200 in-hospital survivors were selected. Patients with beta-blockers showed significantly lower 1-year major adverse cardiac events (MACE), which was a composite of cardiac death, MI, revascularization, and readmission due to heart failure [9.7 vs. 14.3/100 patient-year; hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.72–0.97; P = 0.022). However, this association had a significant interaction with left ventricular ejection fraction (LVEF). Beta-blocker therapy at discharge was associated with lower 1-year MACE in patients with LVEF ≤40% (HR 0.63, 95% CI 0.48–0.81; P < 0.001), and 40% <LVEF < 50% (HR 0.69, 95% CI 0.51–0.94; P = 0.020), but not in patients with LVEF ≥50% (HR 1.16, 95% CI 0.91–1.48; P = 0.234). Conclusions Beta-blocker therapy at discharge was associated with better 1-year clinical outcomes in patients with reduced or mid-range LVEF after AMI, but not in patients with preserved LVEF. These data suggested that the long-term beta-blocker therapy may be guided by LVEF.