AbstractPartial red cell exchange transfusion is used to manage several complications of sickle cell anemia. Reports have stressed the safety, case, and speed of red cell exchange procedures performed with blood cell separators, but little information exists concerning operating conditions for the most efficient removal of hemoglobin S (HbS) containing cells. We performed 13 red blood cell exchange transfusions with the IBM 2997 continuous flow blood cell separator on two previously transfused adult homozygous (SS) sickle cell patients. We used both a single stage and a dual stage disposable pathway and varied rotor speed, collection port, and collection interface independently. The patients' baseline percentage HbS ranged from 28 to 64% (mean = 46%); post exchange values ranged from 19.1 to 46% (mean = 32%). Thirty‐three of 34 specimens collected from the white cell or platelet port showed a higher percentage of HbS in the collection line compared to simultaneous patient samples. Mean enrichment was 9.4% (range = −4.0 to 35.5%). There was an inverse relationship between the hemoglobin concentration and the percentage of HbS in the collected specimens (p = 0.001; N = 45). Differential separation of sickle cells should decrease the volume of blood required for partial red cell exchange of selected SS patie