We report on a 28-year-old patient with transfusion-dependent beta-thalassemia major, who was treated effectively with recombinant human erythropoietin (rHuEpo). rHuEpo promotes the differentiation and proliferation of erythroid cells, induces the production of fetal hemoglobin (HbF), and could be useful in the treatment of some selected transfusion-dependent thalassemia patients. Prior to rHuEpo treatment, the patient was on a regular blood transfusion regimen. Splenectomy did not decrease the transfusion requirements. Additionally, red cell alloimmunization had developed; therefore, we decided to start rHuEpo treatment (Eprex, Jansen Cilag, Greece) in an attempt to improve his anemia and the quality of life. Our patient responded well to rHuEpo treatment and was able to extend the intervals between transfusions from 10-14 to 55-65 days and to sustain a pretransfusion hemoglobin level above 7 g/dl. HbF levels were slightly increased from 55% to 60-65%. Indicators of vascular endothelial activation [serum endothelin-3, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin] were decreased during treatment. rHuEpo was well tolerated without complications. rHuEpo treatment seemed to have had a beneficial effect and to have improved the quality of life in beta-thalassemia major, although it did have a slight effect on HbF levels, suggesting other possible mechanisms of rHuEpo action.