Abstract: Objective To study the effect of alpha lipoic acid(A-LA) on endoplasmic reticulum stress(ERS)-induced myocardial apoptosis in diabetic rats. Methods SD rats were randomly divided into control group, diabetic model group, and A-LA group.A diabetic model was established by intraperitoneal injection with streptozocin(60mg/kg). A-LA group underwent A-LA gastric irrigation(60 mg/kg). Control group and diabetic model group received daily normal saline gastric irrigation. Their blood sugar and cardiac function were tested after 12 weeks. Cell apoptosis was detected by TUNEL. Glucose-regulated expression levels of GRP78 and caspase-12 were measured by Western blotting and immunohistochemistry, respectively. Results The blood glucose level was significantly higher and the damage of cardiac function was severer in diabetic model group and A-LA group than in control group(P< 0.05). The A-LA improved the blood glucose level and cardiac function of diabetic rats. The cell apoptosis level and the expression levels of GRP78 and caspase-12 were significantly higher in diabetic model group than in control group and significantly lower in A-LA group than in control group(P< 0.05). Conclusion A-LA protects cardiac muscle in diabetic rats possibly by decreasing the expression level of GRP78 and caspase-12, and blocking the ERS-initiated opoptotic pathway.