Aim To investigate the roles of reperfusion injury salvage kinase （RISK） signaling pathway and mitochondrial ATP-sensitive potassium channels （mKATP） in the postconditioning effect of adenosine triphosphate （ATP） for rabbits with myocardial ischemia/reperfusion iniury （IRI）. Methods Sixty white male rabbits were exposed to 40 min of ischemia followed by 180 min of reperfusion. Rabbits were intravenously injected 3 mg/kg of ATP （ATP group） or saline （IRI group） immediately after reperfusion within 30 min. The Wortmannin＋ATP, PD98059＋ATP, and 5-hydroxydecanoic acid sodium salt （5-HD）＋ATP groups were respectively injected with Wortmannin （PI3K inhibitor, 0.6 mg/kg）, PD98059 （ERK1/2 inhibitor, 0.3 mg/kg）, and 5-HD （a mKATP blocker, 5 mg/kg） 5 min before ATP administration. Myocardial infarction size was measured by Evans blue and NBT staining. Myocardial apoptosis index was determined by TUNEL methods. Expressions of myocardial Akt, p-Akt, ERK1/2 and p-ERK1/2 were detected by Western blot. Results The myocardial infarction size and apoptosis index were significantly lower in ATP group than those in IRI group, Wortmannin＋ATP group, PD98059＋ATP group and 5-HD＋ATP group （P<0.01）. Western blot showed that the expressions of p-Akt and p-ERK1/2 were significantly higher in ATP group than those in other four groups （P<0.05）.Conclusions ATP postconditioning attenuated IRI by reducing the myocardial infarction size and apoptosis, which is mediated through activation of RISK signaling pathway and opening of mKATP.