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Anti-CD38 therapy causes interference with both the direct and the indirect antiglobulin tests. We describe the experience from an Immunohematology Reference Laboratory and model cost options for providing safe transfusions.Phenotyping, genotyping, and antibody identification orders were retrospectively reviewed in the setting of anti-CD38 therapy. The data were used to model the added cost of transfusion support. Four approaches were evaluated: 1) thiol-treated reagent red blood cells (RRCs) in antibody investigations with K– red blood cell (RBC) transfusions, 2) patient phenotyping or 3) genotyping with antigen-matched RBC transfusions, and 4) a combination of interval thiol-treated RRC antibody investigations with genotype antigen–matched RBC transfusions.Sixty-two patients were identified as receiving anti-CD38 therapy. Thiol-treated RRC antibody investigations (28/62 patients) were favored over genotyping (23/62) and combination testing (11/62). Patient phenotyping failed to detect useful antigen information on eight patients: seven Fyb silencing mutations and one partial e. A thiol-treated RRC antibody investigation was the least expensive testing method for the first transfusion, but four- and five-antigen-matched RBC transfusions were equal in cost within five and 21 transfusion events, respectively.Genotyping provided a more accurate antigen status than phenotyping patient RBCs. Patients requiring long-term transfusion support benefit from antigen matching when matching less than four antigens. Ultimately, the decision to genotype or use thiol-treated RRC antibody investigations will vary for each hospital blood bank.