OBJECTIVE To explore the effect of erythropoietin (EPO) on reperfusion arrhythmias in rats and identify the possible mechanism involved. METHODS Forty-five SD rats were randomized into a sham-operated group and 4 cardiac ischemia/reperfusion (IR) injury groups, which were further divided into IR group, LY294002 group, EPO group, and EPO+LY294002 group. Cardiac IR injury was induced in the 4 IR injury groups by ligating the left anterior descending branch of the coronary artery (LAD) for 30 min followed by reperfusion for 3 h, with subsequent treatments accordingly. The occurrence of arrhythmias was monitored and scored during experiment, and the levels of serum CK-MB and cTnI were detected. The content of MDA in the myocardium was determined by thiobarbituric acid (TBA) method, and the content of SOD by xanthine oxidase method. RESULTS The arrhythmia score in EPO group was significantly lower than those in IR, LY294002 and EPO+ LY294002 groups (P<0.05). The levels of serum CK-MB and cTnI were significantly lower in EPO group than in the other 3 IR groups (P<0.001). The EPO group showed also significantly lower MDA content (P<0.001) and higher SOD content than the other 3 IR groups (P<0.001). CONCLUSIONS EPO at the dose of 1000 mg/kg decreases the incidence of reperfusion arrhythmias in rats, and this effect can be attenuated by LY294002 pretreatment, suggesting that the cardioprotective effect of EPO involves antioxidation mediated by the phosphoinositide 3-kinase (PI3K) pathway.