Background & aims: The present study was undertaken to evaluate the cardioprotective mechanisms of Withania somnifera (Ws), in the setting of ischemia and reperfusion (IR) injury. Methods: Wistar rats were divided into three groups and received orally saline (sham, control IR) and Ws-50 mg/kg (Ws-IR), respectively, for 1 month. On the 31st day, in the rats of control. IR and Ws-IR group, LAD coronary artery occlusion was undertaken for 45 min followed by 1 h reperfusion. Subsequently, all the animals were sacrificed for biochemical., immunohistochemical. {Bax and Bcl-2 protein}, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) positivity and histopathological. studies. Results: Post-ischemic reperfusion injury resulted in significant cardiac necrosis, apoptosis, decline in antioxidant status and elevation in lipid peroxidation in the IR control group as compared to sham. Ws prior-treatment favorably restored the myocardial oxidant-antioxidant balance, exerted marked anti-apoptotic effects {upregulated Bcl-2 (p < 0.001) protein, decreased Bax (p < 0.01) protein, and attenuated TUNEL positivity (p < 0.01)), and reduced myocardial damage as evidenced by histopathologic evaluation. Conclusions: The antioxidant and anti-apoptotic properties of Ws may contribute to the cardioprotective effects. (C) 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.