Description: Background— Liraglutide, a glucagon-like peptide-1 analog, was reported to reduce reperfusion injury in mice. We planned to evaluate the effects of liraglutide on reperfusion injury in patients with acute ST-segment–elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results— A total of 96 patients with ST-segment–elevation myocardial infarction undergoing emergency primary percutaneous coronary intervention were randomized to receive either subcutaneous liraglutide or placebo. Study treatment was commenced 30 minutes before intervention (1.8 mg) and maintained for 7 days after the procedure (0.6 mg for 2 days, 1.2 mg for 2 days, followed by 1.8 mg for 3 days). The salvage index was calculated from myocardial area at risk, measured during the index admission (35±12 hours), and final infarct size measured at 91±5 days after primary percutaneous coronary intervention by cardiac magnetic resonance. At 3 months, the primary end point, a higher salvage index was found in the liraglutide group than in the placebo group in 77 patients evaluated with cardiac magnetic resonance (0.66±0.14 versus 0.55±0.15; P =0.001). The final infarct size was lower in the liraglutide group than that in the placebo group (15±12 versus 21±15 g; P =0.05). Serum high-sensitivity C-reactive protein level was lower in the liraglutide group ( P 〈0.001). During a 6-month follow-up period, no difference was observed in the incidence of major adverse cardiovascular event. Safety and tolerability were similar among the 2 groups. Conclusions— Our study provides evidence that liraglutide improves myocardial salvage and infarct size after ST-segment–elevation myocardial infarction, possibly by reducing reperfusion injury, making it a promising treatment for evaluation in larger trials. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT02001363.