Cardiac damage remains a major cause of mortality among patients with thalassemia major. The detection of alower cardiac magnetic resonance T2* (CMR-T2*) signal has been suggested as a powerful predictor of the subsequent development of heart failure. However, the lack of worldwide availability of CMR-T2* facilities prevents itswidespread use for follow-up evaluations of cardiac function in thalassemia major patients, warranting the needto assess the utility of other possible procedures.In this setting,the determination of left ventricular ejection fraction(LVEF)offers an accurate and reproducible method for heart function evaluation. These findings suggest a reductionin LVEF≥7%, over time, determined by 2-D echocardiography, may be considered a strong predictive tool for thedetection of thalassemia major patients with increased risk of cardiac death. The reduction of LVEF≥7% had higher(84.76%) predictive value. Finally, Kaplan–Meier survival curves of thalassemia major patients with LVEF≥7%showed a statistically significant decreased probability of survival for heart disease (p=0.0022).However, because of limitations related to the study design, such findings should be confirmed in a largelong-term prospective clinical trial.