Caveolin-1-deficient (cav1^-/-) mice display a severely diseased cardiac phenotype with systolic and diastolic heart failure. Accumulating evidence supports a causative role of uncoupled endothelial nitric oxide synthase in the development of these abnormalities. Interestingly, a similar molecular mechanism was proposed for anthracycline-induced cardiomyopathy. Currently, dexrazoxane is approved for the prevention of anthracycline-induced cardiomyopathy. Given the molecular similarities between the anthracycline-induced cardiomyopathy and the cardiomyopathy in cav1 ^-/- mice, we questioned whether dexrazoxane may also prevent the evolution of the cardiac pathologies in cav1^-/- mice. We evaluated dexrazoxane treatment for 6 weeks in cav1^-/- mice and wild-type controls. This study provides the first evidence for a reduced reactive oxygen species formation in the vessels of dexrazoxane-treated cav1^-/- mice. This reduced oxidative stress resulted in a markedly reduced rate of apoptosis, which finally was translated into a significantly improved heart function in dexrazoxane-treated cav1^-/- mice. These hemodynamic improvements were accompanied by significantly lowered proatrial natriuretic peptide levels. Notably, these protective properties of dexrazoxane were not evident in wild-type animals. Taken together, these novel findings indicate that dexrazoxane significantly reduces vascular reactive oxygen species formation cav1^-/-. Because this is paralleled by an improved cardiac performance in cav1^-/- mice, our data suggest dexrazoxane as a novel therapeutic strategy in this specific cardiomyopathy.