Fifteen children with sickle cell disease undergoing long-term erythrocytapheresis were assessed for splenic regeneration using abdominal ultrasound and radionuclide spleen scans. Despite a significant level of reduction of hemoglobin S (HbS), none of the 15 patients showed evidence of splenic regeneration. Comparing our results with other published reports on hypertransfusion therapy in patients with sickle cell disease, it appears that the process of splenic regeneration in these patients is minimal and may depend partly on the intensity of transfusion therapy and the length of time that HbS has been maintained below 20%.