Matrix metalloproteinase-9 (MMP-9) is crucial in tissue remodeling after an adverse cardiac event. In experimental studies, melatonin has been found to attenuate MMP-9 activation. The present study assessed the effects of systemic melatonin administration on the prognosis of patients with acute myocardial infarction (AMI) successfully treated with primary percutaneous coronary intervention, and to examine the effects on MMP-9 levels. We conducted a randomized controlled trial, enrolling patients who underwent primary percutaneous coronary intervention due to AMI. They were assigned to two groups for melatonin or placebo. The primary endpoint was a combined event of mortality and heart failure readmission at 2 years. The secondary endpoint was the levels of MMP-9 after the percutaneous coronary intervention. Ninety-four patients were enrolled, 45 in the melatonin group and 49 in the control group. At 2 years of follow-up, 13 (13.8%) patients suffered the primary endpoint (3 deaths and 10 readmissions due to heart failure), 3 patients in the melatonin group and 10 in the placebo group. The difference in the restricted mean survival time was 87.5 days ( = 0.02); HR = 0.3 (95% CI 0.08-1.08; = 0.06); Log-rank test 0.04. After controlling for confounding variables, melatonin administration reduced MMP-9 levels to 90 ng/mL (95% CI 77.3-102.6). This pilot study demonstrated that compared to placebo, melatonin administration was associated with better outcomes in AMI patients undergoing primary percutaneous coronary intervention.