Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death.We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixtyeightpatients with thalassemia major followed for at least 5 years who received continuous monotherapy withdeferoxamine (N = 108) or deferiprone (N = 60). The statistical analysis, using the generalized estimatingequations model, indicated that the group treated with deferiprone had a significantly better left-ventricularejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p = 0.002).The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number ofmitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might crossinto heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function.Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricularfunction over time in comparison with deferoxamine treatment. However, because of limitations related tothe design of this study, these findings should be confirmed in a prospective, randomized clinical trial.