Doxorubicin (DOX) has been used in a variety of human malignancies for decades, in particular of lymphoma. But increased cardiomyocyte apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) generates cardiovascular protective effects by heme oxygenase-1(HO-1)-mediated mechanism. The present study was designed to determine whether RES protected cardiomyocyte against apoptosis through induction of HO-1 in lymphoma nude mouse in vivo. After being developed into lymphoma model, 40 male Balb/c nude mice were randomized to one of the following four treatments (10 mice per group): control, DOX, DOX + RES and DOX + RES + HO-1 inhibitor (zinc protoporphyrin IX, ZnPP). The results showed that DOX injection markedly decreased the body weight, the heart weight and the ratio of heart weight to body weight, but inversely increased cardiomyocyte apoptosis and the level of serum lactate dehydrogenase and creatine kinase. Moreover, DOX injection attenuated HO-1 expression and enzymatic activity as well as increased P53 expression, modulated Bcl-2/Bax expression and enhanced caspase 3 activity. These cardiotoxic effects of DOX were ameliorated by its combination with RES. However, the protective effects of RES were reversed by the addition of ZnPP. Taken together, it is concluded that HO-1 plays a core role for protective action of RES in DOX-induced cardiomyocyte apoptosis in lymphoma nude mice.