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This study was to investigate whether Semen Cassiae extract reduces myocardial ischemia and reperfusion (MI/R) injury.Methods: The high-fat diet-fed streptozotocin (HFD-STZ) rat model (type 2 DM model) was developed.were given the extract mixed into the fodder of the concentration of 50 g crude herbal medicine/kg BW for 14 days.And MI/R (30 min/4 hrs) was performed.Results: Treatment of diabetic rats with semen cassiae extract improved ±LVdP/dtmax, reduced infarct size and apoptosis (n=8, P<0.05), and increased the antiapoptotic protein Akt and ERK1/2 expression and phosphorylation levels (n=3, P<0.05).Pretreatment with wortmannin or PD98059 significantly blocked Akt and ERK1/2 phosphorylation and inhibited the cardioprotective effects induced by extract feeding.But semen cassiae extract treatment did not show any effect on MI/R injury in normal rats.Conclusions: Semen Cassiae improves myocardial function and reduces MI/R-induced injury in diabetic but not normal rats, possibly attributed to the triggered cell survival signaling Akt and ERK1/2.