Abstract Introduction/Objective Red cell exchange (RCE) is utilized as a therapeutic or prophylactic procedure for patients with sickle cell disease (SCD). When performing RCE, three hematocrits (Hct) are taken into account: pre-procedure and goal Hct for the patient and average Hct (avg-Hct) of the transfused RBC units. Although there is no definitive community consensus, many transfusion services employ RBC unit avg-Hct of 55% per available guidance. Our center anecdotally observed that utilizing RBC unit avg-Hct of 55% often resulted in post-procedure patient Hcts higher than intended goal Hct, potentially causing hyperviscosity. This study aims to examine the effect of changing the avg-Hct from 55% to 60% on the accuracy of post-procedure HCTs, with the 60% avg-Hct employed based on prior quality studies of RBC units at our facility. Methods/Case Report We performed a retrospective chart review for SCD patients receiving chronic, prophylactic RCE at a large academic hospital, collecting the following for each procedure: goal procedure Hct, number of RBC units exchanged, avg-Hct used, and pre-/post-procedure patient Hcts. Differences between goal Hcts and post- procedure Hcts for each procedure in the avg-Hct=55% and avg-Hct=60% groups were calculated. Next, mean calculated differences for both groups were compared using a two-sample t-test (P<0.05 was considered significant). Results (if a Case Study enter NA) From 1/2023–2/2024, 293 prophylactic RCEs were performed for SCD patients. Median number of RBC units per procedure was 7, with 51% of procedures (n=149) employing unit avg-Hct=55%, while 49% of procedures (n=144) used a unit avg-Hct=60%. Post-procedure patient Hct and goal Hct differences were statistically different according to unit avg-Hct values utilized (mean difference=1.31% for avg-Hct=55% vs mean difference=0.52% for avg-Hct=60%; P<0.0001). Conclusion Changing our protocol to use RBC unit avg-Hct=60% resulted in post-procedure patient Hcts significantly closer to intended goals. Utilization of a more accurate average-Hct value has a substantial impact on post-procedure Hct in RCEs and may limit adverse events.