BACKGROUND Red blood cell (RBC) transfusions remain essential in the treatment of patients with sickle cell disease (SCD) and β‐thalassemia. Alloimmunization, a well‐documented complication of transfusion, increases the risk of delayed hemolytic transfusion reactions, complicates crossmatching and identifying compatible units, and delays provision of transfusions. Guidance is required to optimize the RBC product administered to these patients. STUDY DESIGN AND METHODS An international, multidisciplinary team conducted a systematic review and developed, following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, recommendations to assist treating physicians and transfusion specialists in their decision to select RBCs for these patients. RESULTS Eighteen studies (17 clinical studies and one cost‐effectiveness study) were included in the systematic review. The overall quality of the studies was very low. In total, 3696 patients were included: 1680 with β‐thalassemia and 2016 with SCD. CONCLUSION The panel recommends that ABO D CcEe K–matched RBCs are selected for individuals with SCD and β‐thalassemia, even in the absence of alloantibodies, to reduce the risk of alloimmunization. In patients with SCD and β‐thalassemia who have developed clinically significant alloantibodies, selection of RBCs antigen negative to the alloantibody is recommended, if feasible. In these patients, selection of more extended phenotype‐matched RBCs will likely reduce the risk of further alloimmunization. However, given the limited availability of extended phenotype‐matched units, attention should be given to ensure that a delay in transfusion does not adversely affect patient care.