Chronic transfusion therapy, while effective in preventing recurrent stroke, is associated with the long term complication of iron overload. To prevent further increase in iron burden in long term transfusion patients and to avoid iron overload in new patients, we converted six patients from simple/partial transfusion to pheresis. As previously reported, pheresis is effective in adequately controlling hemoglobin (Hb) S levels and slowing development of iron overload. However, blood usage and donor exposure increased 60% when Hb S levels were maintained at 40% pre-pheresis. The goals of pheresis were changed to determine if maintaining Hb S at 50% reduces blood exposure, decreases visits and is not associated with complications. Pheresis was performed on a COBE Spectra™ system as previously described. All patients but one were transfused for >2 years (mean 10) prior to pheresis. Time on pheresis ranged from 10-24 months (mean 15 mos.). Desferal was continued in all patients (3) using chelation prior to pheresis. Patients on the new pheresis protocol were compared to their prior experience with traditional transfusion for: 1)complications, 2)recurrent CVA, 3)serum ferritin, 4)volume of packed red blood cells (PRBC) used, 5)donor exposure and 6)number of visits. Results show: 1)no significant complications, 2)no recurrent CVA, 3)iron load remained stable as measured by serum ferritin (one patient begun on pheresis <1 year into traditional transfusion maintains a ferritin≈200ng/ml 24 months into pheresis), 4)volume of PRBC with pheresis was 212 vs 142 ml/kg/yr traditional transfusion, 5)Donor exposure was 47 units/year with pheresis vs 29 traditional, and 6)number of visits/year decreased by three for pheresis. Despite increased blood exposure with pheresis no patient has developed alloantibodies or any infectious complications. Results show pheresis is effective in adequately maintaining Hb S levels and slowing development of iron overload. Our experience suggests pheresis is most effective if instituted early in a transfusion program. If the problem of venous access in younger patients can be overcome, this technique could have a significant impact on length and quality of life for chronic transfusion patients.