A delayed hemolytic transfusion reaction (DHTR) is a potential complication for patients with sickle cell disease (SCD) who develop red blood cell (RBC) alloimmunization to foreign antigens from allogeneic transfusions, potentially resulting in life-threatening hemolytic anemia between 24 hours and 28 days after the transfusion. Guidelines have suggested obtaining an extended RBC antigen profile by genotyping in patients with SCD to provide increased accuracy for antigen matching. We present a pediatric patient with SCD and a rare RBC phenotype that was not identified by serology who developed DHTR after her second lifetime transfusion and highlight the potential advantages of molecular genotyping. She was successfully managed by transfusion with least incompatible packed RBCs and aggressive medical management per American Society of Hematology clinical guidelines. Molecular genotyping is advantageous over serologic phenotyping because it can provide additional antigen information, such as increased accuracy for C antigen determination and Fyb antigen matching. Having RBC genotyping results on file for patients with SCD can facilitate care in two ways-by preventing alloimmunization with potential hemolytic transfusion reaction and by responding rapidly to request rare donors when complicating antibodies arise.