Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis. Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5– 2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr. Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was 4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P 33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts. Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.