Delayed hemolytic transfusion reaction (DHTR) is a complication appearing a few days to weeks due to alloimmunization following packed red blood cells (RBCs) transfusion, a pregnancy, or transplantation. Hyperhemolysis syndrome (HS) is a severe form of DHTR defined by a drop of hemoglobin to a level lower than before the transfusion, reflecting a destruction of the patient’s own RBCs not presenting the targeted antigen as well as the transfused RBCs. Usually seen in sickle cell disease (SCD) patients, HS remains very rare in patients without a hematologic disorder. We report the case of an 82-year-old Caucasian woman who presented with a DHTR with HS after being transfused packed RBC twice in the context of rectal bleeding. The patient was not known for any hemoglobinopathy and did not have a history of massive transfusions nor multiple pregnancies putting her at risk of alloimmunization. Our patient developed anti-C, anti-Fy
a
and anti-Jk
b
antibodies, known to be harmful antibodies. First line of treatment after avoidance of further transfusions is intravenous immunoglobulins for 3 to 5 days and high-dose corticosteroids. Exceptional in the non-SCD population, this complication should be recalled by clinicians as it can be fatal if not treated appropriately. We performed a review of the literature using the words “delayed hemolytic transfusion reaction” and “hyperhemolysis syndrome” for similar cases. Finally, we describe how to diagnose, manage, and prevent this potentially fatal complication, which is still underrecognized even within the SCD population.