As a therapeutic treatment for sickle cell disease, red blood cell (RBC) exchange rapidly removes unwanted hemoglobin (Hgb) S and C and replaces it with donated RBC units containing mainly Hgb A. Determining how much blood to deliver to reach the targeted goal, however, requires laboratory testing for the current measure of abnormal hemoglobin. If results are unknown prior to the start of the procedure, especially in emergent situations, the level must be estimated. We investigated to what degree these estimates led to inappropriate overtransfusion or undertransfusion in our patient population. This was a retrospective, observational study from 2011 to 2016 of patients who had completed one or more RBC exchange procedures in the inpatient setting at a large academic medical center. The following information was obtained: history of disease, number of procedures received, emergent status of procedures, number of RBC units per procedure, goal Hgb S+C percentage, goal fraction of cells remaining (FCR), and Hgb S+C percentages measured pre- and postprocedure. Procedures that lacked any of the latter three pieces of information were not included in the analysis. Estimated preprocedural Hgb S+C percentage was calculated by dividing the Hgb S+C goal by the FCR. Overtransfusion and undertransfusion were determined by comparing the original FCR to an FCR calculated using the actual preprocedural and goal Hgb S+C percentages. During the study period, 378 RBC exchange procedures were assessed. Three primary groups of procedures were evaluated: emergent procedures with unknown preprocedural Hgb S+C percentage (E-U), nonemergent procedures with unknown preprocedural Hgb S+C percentage (NE-U), and procedures with known preprocedural Hgb S+C percentage (Kn). The percent difference between the estimated and actual preprocedural Hgb S+C levels was calculated for each procedure. The median difference (and range) for the E-U, NE-U, and Kn groups was 26.6% (–9.8%-270.4%), 1.6% (–33.5%-311.0%), and 1.3% (–19.5%-118.0%), respectively. The E-U group was significantly different from the other two groups (P < .0001), but the NE-U group was not different from the Kn group (P = .16). Undertransfusion occurred in 14% of procedures by a total of 38 RBC units, and overtransfusion in 39% of procedures by a total of 167 RBC units. Approximately 1/2 of the excess 167 units came from emergent procedures, despite comprising less than 20% of the total procedures. More than half of RBC exchange procedures (53%) resulted in the patient receiving an incorrect number of RBC units, mostly overtransfusion attributable to emergent procedures in which the lab results were still pending by the time the procedures began. These results suggest that a rapid turnaround time method should be available to measure abnormal hemoglobin levels prior to the start of RBC exchange.