Abstract: AIM To evaluate the protective action of melatonin (Mel) against myocardial ischemia/reperfusion (MI/R) injury and its association with endoplasmic reticulum stress (ER stress) level. METHODSNinety male Sprague Dawley rats (180-220 g) were subjected to myocardial ischemia/reperfusion (MI/R, I 30 min, R 6 h) operation by occluding the left descending artery and were randomly divided into three groups: MI/R+V (absolute alcohol diluted in sterile saline to 0.1 mol/L, 1 ml/d, 7 d before MI/R; 1 ml/d, 15 min before reperfusion, ip.), MI/R+Mel ［10 mg/(kg·d), 4 weeks before MI/R］ and sham (rats undergoing the same surgical procedures without tying the suture). After the 4-h reperfusion, ER stress marker GRP78 (glucose regulated protein78), CHOP (CCAAT/enhancer-binding protein homologous protein) and apoptosis-related protein were measured. After the 6-h reperfusion, serum LDH and CK levels, apoptotic index and infarct size were detected. After the 24-h reperfusion, cardiac functions were evaluated. RESULTSRats treated with Mel for 4 weeks showed markedly improved cardiac functions, lower serum LDH and CK level, decreased apoptotic index, reduced infarct size, down-regulated GRP78 and CHOP expressions and decreased apoptosis-related protein expressions (all P<0.01). CONCLUSIONMelatonin treatment ameliorates MI/R injury by reducing ER stress, thus improving post-MI/R cardiac functional recovery.