The evaluation of a transfusion reaction is a complex process aimed at detecting acute intravascularhemolysis through clinicalinvestigation and serologic assays. However, several variables can complicate testing in the postreaction period and obscure an accurate diagnosis. We report a patient with myelodysplasia who was noted to have a febrile response to a unit of red blood cells (RBCs). Testing of the posttransfusion specimen raised concerns for a hemolytic transfusion reaction when the patient's RBCs demonstrated a positive direct antiglobulin test (DAT) and the plasma showed incompatibility with the donor RBCs. Further evaluation revealed that: (1) antibiotic treatment induced a "false" positive DAT in the patient, and (2) donor RBCs were coated with an autoantibody causing them to appear incompatible during postreaction testing. Thus, if donor and recipient incompatibility is encountered during a transfusion reaction evaluation, testing of donor RBCs may help resolve issues of serological incompatibility.