A hemolytic transfusion reaction due to anti-Fy3 is reported in an African American patient with no history of sickle cell disease. This 82-year-old African American woman received two units of RBCs for anemia (Hab 7 g/dL) on admission for a left hip fracture. On hospital Day 7, the patient underwent left hip endoprosthesis surgery; she received two units of RBCs on the second postoperative day due to Hb of 6.1 g/dL. Her urine was dark during surgery and postoperatively. Her posttransfusion plasma was red. Her Hb dropped from 8.4 to 6.4 g/dL over 24 hours after the transfusion. Her total bilirubin rose to 4.0 mg/dL, with and LDH value of 1558 U/L and a haptoglobin of 10.9 mg/dL. Both the antibody detection test and the DAT were positive. An anti-Fy3 was identified in the serum and in the eluate. To the best of our knowledge, this is the first case of acute intravascular hemolysis due to anti-Fy3 in a patient without sickle cell disease.