Delayed hemolytic transfusion reactions (DHTRs) are mediated by blood group antibodies that undergo anamnestic increases following antigen reexposure. Available options for the treatment or prophylaxis of DHTRs are limited. We report the use of automated red blood cell exchange (ARE) to limit hemolysis associated with an emerging DHTR. Following transfusion of 12 red blood cell units, a family member's comments led to the discovery of a patient's history of 4 alloantibodies (anti-E, anti-c, anti-Fy(a), and anti-M). Testing revealed that all 12 units were incompatible for at least 1 antigen. Six days after transfusion, the patient developed a newly positive antibody screen and direct antiglobulin test (DAT) result. To prevent further hemolysis, ARE was performed to replace incompatible red blood cells with antigen-negative units. After ARE, the patient's DAT results were negative and he was discharged without demonstrating symptoms of hemolysis. This case illustrates the use of ARE to limit hemolysis and prevent symptoms of a DHTR.