An acute hemolytic transfusion reaction is a potentially fatal complication resulting from the transfusion of mismatched blood products. Symptoms vary from mild to severe depending on how much incompatible antigen was transfused and the nature of the recipient's antibodies. There is no consensus agreement of appropriate management other than discontinuing the transfusion and basic supportive methods including adjunctive pharmacologic agents. A 40-year-old male presented with a gunshot wound to the upper torso. During surgery, the O+ patient lost 1.3 L of blood and postoperatively was inadvertently given one unit of A+ packed red blood cells. The blood bank noticed the error and notified the floor within the hour. An acute hemolytic transfusion reaction had progressed to shock and disseminated intravascular coagulation within hours. The clinical course continued to decline despite a norepinephrine drip and a red blood cell exchange transfusion was implemented within 5 h of the mismatched transfusion. The patient's hematological parameters and clinical markers improved and he was eventually discharged in stable condition. An adjunctive red blood cell exchange transfusion may be useful when treating an ABO-incompatible acute hemolytic transfusion reaction if there has been a large volume mismatched transfusion and a poor clinical response to basic supportive methods.