Background: It is unknown whether chronic erythropoietin (EPO) treatment is able to normalize hemoglobin (Hb) levels and ameliorate cardiac remodeling avoiding blood transfusions in uremic blood transfusion-dependent patients with β-thalassemia minor (β-thal). Methods: In 12 hemodialysis (HD) patients with β-thal, requiring blood transfusions despite EPO therapy, we planned to increase Hb levels up to the target levels (11–12 g/dl) within a one-year period by administering progressively higher doses of EPO (correction phase). We also planned to maintain the Hb target for an additional year (maintenance phase). Results: In the year before the study, patients required 3.3 ± 0.9 units of packed red blood cells. At baseline, the Hb level obtained with an EPO dose of 212 ± 73 U/kg/week i.v. was 8.2 ± 0.8 g/dl. The EPO dose was gradually increased within the first year up to 458 ± 78 U/kg/week at month 12 (correction phase) and then significantly tapered down during the maintenance phase (390 ± 54 U/kg/week at month 24). During the correction phase, the Hb levels markedly increased (11.1 ± 0.3 g/dl at month 12) and did not change in the maintenance phase. No blood transfusion was required throughout the 2 years of follow-up. Left ventricular (LV) mass index progressively decreased from the basal value of 144 ± 12 to 124 ± 11 g/m<sup>2</sup> in the first year and normalized in all patients at month 24 (109 ± 12 g/m<sup>2</sup>, p < 0.001); this occurred in the absence of any change of LV cavity volume index (<90 ml/m<sup>2</sup>). Conclusions: In HD transfusion-dependent patients with β-thal, the administration of high EPO dose for 2 years permits the attainment and the maintenance of Hb targets without blood transfusions. This therapeutic approach permits a complete remission of concentric LV hypertrophy without any adverse effects on the vascular system.