Iron overload is an inevitable consequence of chronic red cell transfusions without erythrocytapheresis or chelation therapy. The effectiveness of partial manual exchange, a technique used to slow iron loading, has not been evaluated. We evaluated all children with sickle cell disease (SCD) receiving chronic transfusion to identify chelation-naive subjects who had quantitative liver iron concentration (LIC) studies. Seventeen chelation-naive children with SCD received a median of 29 transfusions before first LIC determination. Serum ferritin concentrations were assessed before each transfusion. The mean volume of blood phlebotomized before each transfusion was 5.1±1.8 mL/kg, which cumulatively resulted in a calculated median of 35.0 mg/kg iron removal. Using linear regression, pretransfusion phlebotomy resulted in a statistically significant reduction in ferritin (−8.8 ng/mL of ferritin for each mg/kg of iron phlebotomized, P=0.02). A reduction in LIC from pretransfusion phlebotomy could not be established (P=0.4). Partial manual exchanges appear to be an effective strategy for slowing the pace of iron loading in the setting of chronic transfusion for SCD.