A 28-year-old woman with sickle cell anemia suffered a left hemispheric cerebrovascular accident associated with severe right-sided weakness during a delayed hemolytic transfusion reaction owing to anti-rh' (C) and anti-S. The anti-rh' (C) had been identified four years earlier at a different hospital but neither the patient, her family, nor any member of the staff of the hospital where she was transfused was aware of this information. It is postulated that spherocytes, formed during hemolysis, could slow capillary flow, thereby increasing red cell sickling and producing vaso-occlusion. The patient had no clinically apparent neurologic complications during the preceding 24 years and has had no further neurologic events during the subsequent 20 months. This patient's reaction underscores the compelling need for sensitive pre-transfusion tests as well as the obligation to inform patients and their families of the presence and potential consequences of alloantibodies in the event of future transfusion.