Recommended transfusion strategy for SCD patients. All recommendations are based on the results of the serum antibody screening test results and the extended RBC phenotype of the patient. For patients with no detectable antibodies, no known previous antibodies, and no abnormal RBC phenotype, transfusion of leukoreduced, cross-matched RH/KEL-compatible RBC units is recommended. When antibodies are identified at the screening test or known by history, 2 scenarios can be encountered: (1) The corresponding antigen is not expressed on patient RBCs; therefore, the antibody is an alloantibody (Ab = Allo), and hence antigen-negative RBCs should be transfused. (2) The corresponding antigen is expressed on patient RBCs, and serologic and/or molecular studies are needed to determine whether the antibody is an alloantibody produced in a partial antigen carrier or an autoantibody (Ab = Auto). If an alloantibody, and there are available donor units, compatibility should extend to other common nonexpressed antigens. If an autoantibody, matching for the corresponding antigen is unnecessary. For the phenotype of the patient, 2 situations should be considered: (1) One situation is the presence of a weak antigen, where molecular analysis will be needed to determine whether it is a partial antigen. If the patient has no detectable antibodies, transfusion with an antigen-negative unit is preferred, although antigen-positive RBCs can also be issued because the risk of alloimmunization in patients with weak antigens has not yet been determined. However, close monitoring of possible immunization is needed if antigen-positive units are transfused. (2) Another situation is the presence of a rare phenotype, where availability of high frequency antigen-negative units is the determining factor for the transfusion strategy. If the patient is already immunized against the high-frequency antigen, antigen-negative units are recommended for transfusion. If no rare units are available, the benefit/risk ratio of transfusion has to be considered. For patients who are not yet immunized against high incidence antigens, transfusion of antigen-negative units is also recommended if such units are not in short supply. Otherwise, the standard RBCs for SCD can be issued, and the patients should be monitored closely. Given that antigen-negative units for patients with rare phenotype are by definition in short supply, transfusion management of these patients can become extremely challenging, and we recommend that the risk/benefit ratio of alternative treatments, such as hydroxyurea (hydroxycarbamide) for adult patients or bone marrow or cord blood transplantation for children, is discussed with such patients.