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Recent advances in the treatment of patients with thalassemia major have centered around the removal of iron from individuals already overloaded due to repeated transfusions. In this report we present therapeutic maneuvers designed to decrease the rate of iron accumulation. We demonstrate that the persistent maintenance of hematocrits above 35% (“supertransfusion”) is not associated with an increased transfusion requirement because it produces a decrease in whole blood volume (21% +/- 2%). Supertransfusion is also associated with normalization or even prolongation of plasma iron turnover. In addition, we describe a method for obtaining units of blood from normal donors that contain primarily young red cells (“neocytes”). These cells have prolonged in vivo survival as measured by the interval between transfusions (30 +/- 2.5 days to 43 +/- 4.5 days) and 51Cr red cell survival (43.8 days versus 27.8 days). Supertransfusion with neocytes is effective in decreasing the rate of iron accumulation in thalassemia.