Abstract: Alloimmunization is a significant complication of blood transfusion, especially in sickle cell patients, and may lead to a delayed hemolytic transfusion reaction (DHTR). DHTR is defined as evident hemolysis and a positive direct antiglobulin test (DAT) 24 h to 28 days posttransfusion with either a positive eluate or a newly identified alloantibody in the plasma. Hyperhemolysis syndrome (HS) is a fatal form of DHTR in which the posttransfusion hemoglobin (Hb) level is less than the pretransfusion Hb level. In this case series, we have reported three cases of alloimmunized sickle cell disease patients with clinically significant DHTR. The second case is typical of HS. All three cases were DAT positive, alloimmunized with multiple alloantibodies, and had substantial hemolysis posttransfusion. In this series, we have provided an algorithmic approach to resolve such complex immunohematological problems and have highlighted some of the limitations of serology methods. High-dose corticosteroid and intravenous immunoglobulin prove to be an effective treatment for DHTR.