Abstract Background and aim of the study: Heart failure in the western world is a major health-care issue. In order to validate novel surgical or pharmacological treatments, reproducible animal models of left ventricular dysfunction are necessary. In the current study, we report our data and experience with a model of toxin-induced heart failure in the sheep. Methods: Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until standard echocardiographic and tissue Doppler imaging detection of myocardial systolic dysfunction. The animals were assessed 1 month later and harvested. Indices of cardiac function from baseline to last day of protocol were recorded and their differences were evaluated by a Wilcoxon rank test for paired data. Results: Ten sheep received 2.5 ± 0.7 intracoronary injections of a cumulative dose of 88.8 ± 25 mg/m2 doxorubicin. All available parameters demonstrated signs of severe cardiac dysfunction with statistical significance. All hearts demonstrated severe histological lesions, some of which were consistent with doxorubicin-induced toxicity. Conclusions: The present study shows that this ovine model is reproducible and stable. It can therefore be relevant to the study of chronic heart failure. It will be incorporated in our future studies concerning novel treatments (such as cell therapy) of nonischemic dilated cardiomyopathy.