ABSTRACT Red blood cell transfusion remains a life-saving therapy for patients with sickle cell disease (SCD). A major problem is the high rate of alloimmunization (antibody formation against transfused red cells) that occurs in transfused patients with SCD. Alloimmunization leads to delays in care, increases costs, and makes transfusion therapy unsafe and impossible for some patients. The most common antibodies formed by patients with SCD are directed against the Rh blood group system. Genetic diversity in Rh antigens in patients and blood donors of African descent contributes to this high incidence and complexity of antibodies found in patients with SCD. Recent studies performed by our group and others demonstrate RH genetic variants in patients and donors is a major risk factor leading to Rh alloimmunization. Routine blood bank assays can not identify these variants, so although Rh-matched red cells are transfused to patients with SCD, they would only be truly Rh-matched with DNA-based matching. Genetic matching of donor units at the RH loci may prevent Rh alloimmunization but no clinical trials have been conducted. Major barriers are the current cost of RH genotyping as well as inventory and data management of donor genotypes to identify RH matched units for patients. The major goal of this proposal is to perform pilot clinical studies to provide RH genotype matched red cells to chronically transfused patients with SCD. We will determine the feasibility of identifying adequate genotype matched donor units in real clinical practice, identify barriers, and prospectively monitor patients for Rh alloimmunization. A second goal for this proposal is to apply new technologies to improve our knowledge of the two RH genes, RHD and RHCE, which due to their high sequence similarity, currently makes it challenging to apply low cost sequencing methods to provide RH genotype matched red cells for all patients with SCD. In this application, we propose three integrated aims that can address the current challenges of transfusion therapy for SCD, and will drive the field forward by providing innovative solutions to these current obstacles.