Transfusion of patients with sickle cell disease (SCD) has been a challenge in clinical transfusion medicine, especially when the required donor RBCs must be U- and negative for high-prevalence Rh phenotypes (hr(B), hr(S)). It is now possible to genotype donors to identify or confirm Uvar and U- phenotypes, as well as Rh hr(B)- and hrS- phenotypes, and to characterize the different RH backgrounds found in these donors. In a preliminary study of donors registered in the American Rare Donor Program, twelve different RH backgrounds were identified in eighteen hr(B)- or hr(S)- donors. These results, summarized in the current report, confirm the heterogeneous nature of these phenotypes and are relevant for selection of donor units for patients with antibodies to high-prevalence Rh antigens. Not all phenotypically similar units will be compatible, and matching the Rh genotype of the donor to the patient is important to prevent further Rh sensitization. Most donors referred were hr(B)- and carry at least one hybrid RHD-CE(3-7)-D gene that encodes a variant C antigen linked to RHCE*ceS that encodes the VS+V- phenotype. Surprisingly, the majority of donors were heterozygous, some even carrying conventional alleles, suggesting that the loss of expression of the hr(B) epitopes on RBCs is a dominant phenotype. Although antigen-matching of patients with SCD with donors for C, E, and K antigens has decreased the incidence of alloimmunization, some patients still become immunized to Rh antigens, indicating the units were not truly matched. RH genotyping can identify those patients with SCD who carry RH alleles that encode altered C, e, or D who are at risk for production of "apparent auto" and alloantibodies to Rh antigens. RH genotyping of alloimmunized patients with SCD, partnered with genotyping of donors, can identify compatible units that would also eliminate the risk of further Rh alloimmunization.