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In children with sickle cell disease (SCD), primary and secondary prevention of strokes require indefinite regular blood transfusion therapy. The risks associated with repeated transfusions include alloimmunization and increased donor exposure. The Charles Drew Program is a directed blood donor program designed to lower donor exposure, decreasing the associated complications of transfusion; however, no evidence exists demonstrating the magnitude of the benefit to the recipient. Further, the use of extended red blood cell (RBC) antigen matching for C, E, and K has been well documented in a clinical trial setting but not extensively evaluated in a standard care setting. The goal of this study is to assess the effectiveness in reducing alloimmunization when matching for C, E, and K and the magnitude of the decrease in donor exposure in a directed blood donor program. The rate of alloimmunization and reduction of donor exposure were determined during the course of 1 year in a cohort of children with SCD who received regular directed donor blood transfusions. A total of 24 recipients were in the program, 16 females and 8 males, 4 to 20 years of age. During 2008, alloimmunization was 0 percent and donor exposure was reduced by 20 percent, compared with usual care. Extended RBC antigen matching has the same benefit as in a clinical trial setting for patients with SCD receiving blood transfusion therapy. Despite significant effort, we only achieved a modest decrease in donor exposure and cannot determine the immediate benefit of a directed blood donor program.