A case of hyperhemolytic transfusion reaction attributable to anti-Fy3 in a 30-year-oldAfricanAmerican woman with a history of sickle cell disease is reported. The patient was admitted for vaso-occlusive sickle cell crisis and received 4 units of packed RBCs secondary to worsening symptomatic anemia (Hb 5.0 g/dL). On admission, the patient's antibody screen and identification showed anti-V and anti-E, and her antibody history included anti-E,-C,-Jk(b),-N, -V,-S,-Sl(a), and a cold agglutinin with possible anti-I specificity. A DAT performed on her RBCs was negative. RBC units that lacked E, C, Jk(b), N,V, and S were transfused. Posttransfusion Hb was 8.9 g/dL. On day 10 she developed a fever of 103 degrees F, and on day 11 her Hb decreased to 6.4 g/dL. She complained of severe back pain and dark urine. In addition, she became hypertensive, tachycardic, and jaundiced. The DAT indicated the presence of IgG on the patient's RBCs. Anti-Fy3 was identified in the serum and eluate. During the next 24 hours, her Hb decreased to 2.4 g/dL. The LDH level was 1687 U/L, and her reticulocyte count was 2.6%. A delayed hemolytic transfusion reaction with hyperhemolysis secondary to anti-Fy3 was suspected and was successfully treated with IVIG and high-dose prednisone. To the best of our knowledge, this is the first published case of hyperhemolysis in sickle cell disease attributable to anti-Fy3.