Despite intense iron-chelation therapy, the life expectancy of patients with beta-thalassemia major (beta-TM) is still limited by the occurrence of heart failure. In the present study, we sought to evaluate the prognostic significance of several clinical factors on the outcome of heart failure or arrhythmias in patients with beta-TM. The study group consisted of 131 consecutive young patients with beta-TM (71 men aged 21+/-4 years, 60 women aged 22+/-5 years) who were initially examined during 1995. The clinical and vital statuses of all patients were biannually reviewed from 1995 to 2004. Cox proportional hazards models were used to evaluate the association of the occurrence of death or nonfatal events due to heart failure or arrhythmias with clinical factors (systolic and diastolic blood pressures), echocardiographic factors (left and right ventricular diameters, left atrial and aortic root dimensions, left ventricular ejection fraction), electrocardiographic factors (T-wave inversion in leads V1-V3, QRS duration, heart rate), and serum ferritin levels, after controlling for age, sex, and body mass index. During the follow-up, 11 men (16%) and 5 women (8%) had an event (men versus women, P = .212). The age-adjusted event rate was 16 events per 913 person-years (2%). The presence of T-wave inversion in right precordial leads (hazard ratio = 3.06; 95% confidence interval [CI], 1.1-8.8), increased heart rate (hazard ratio = 1.28; 95% CI, 1.03-1.58), decreased aortic root diameter (hazard ratio = 0.84; 95% CI, 0.73-0.96), and decreased ejection fraction (hazard ratio per 1% change = 0.95; 95% CI, 0.91-0.99) were associated with a higher risk for a cardiac event. We revealed that the presence of T-wave inversions, increased heart rate, low ejection fraction of the left ventricle, and decreased aortic root diameter appear to confer higher risk for cardiac events in young patients with beta-TM.