Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the long‐term and explain in part the delayed onset of heart dysfunction. DOXO‐EMCH a 6‐maleimidocaproyl hydrazone derivative of doxorubicin, is an albumin binding prodrug which has entered clinical trials because of its superior antitumor and toxicological profile. In the present work, we examined the chronic cardiotoxicity of DOXO‐EMCH in direct comparison with doxorubicin. Rats (11 weeks of age) were treated with intravenous doxorubicin (0.8 mg/kg weekly for 7 weeks), an equimolar dose of DOXO‐EMCH (1.1 mg/kg), or with 3.3 mg/kg of DOXO‐EMCH. Controls received saline. Animals were euthanized at 48th week. Rats exposed to doxorubicin had a severe clinical, and histopathological cardiomyopathy with depressed myocardial activity of cytochrome c‐oxidase (COX, 26% of controls), reduced expression of the mtDNA‐encoded COX II subunit, decreased mtDNA copy numbers (46% of controls), and high levels of malondialdehyde and superoxide (787% of controls). All parameters were highly correlated with myocardial damage. Both DOXO‐EMCH groups did not differ from controls with regard to clinical symptomatology, mortality and mitochondrial enzymes, although the myocardia of the high‐dose group had slightly increased histopathological abnormalities, depressed mtDNA copies (74% of controls) and elevated superoxide levels (347% of controls). Doxorubicin‐exposed hearts and to a lesser extent the myocardia of both DOXO‐EMCH groups contained mtDNA‐deletions. In summary both DOXO‐EMCH doses were superior over doxorubicin with respect to clinical and histopathological evidence of cardiomyopathy, myocardial COX‐activity, COX II expression, mtDNA‐content, mtDNA mutation loads and superoxide production in rats. © 2006 Wiley‐Liss, Inc.