BACKGROUND: The development of RBC autoantibodies resulting from or associated with allogeneic blood transfusions (i.e., RBC autoimmunization) is not a well-recognized complication of RBC transfusions. STUDY DESIGN AND METHODS: The presentation, laboratory evaluation, clinical course, and management of two patients whose autoimmune hemolytic anemia followed allogeneic blood transfusion and occurred in association with the development of one or more alloantibodies is described. A retrospective analysis was performed of our blood-bank records over 1 year to determine the frequency of RBC autoimmunization associated with alloimmunization. RESULTS: Out of 2618 patients who had a positive DAT or IAT, 121 were identified with RBC autoantibodies; 41 of these patients had both allo- and autoantibodies to RBC antigens, whereas the remainder, 80, had only autoantibodies. At least 34 percent (12/41) of these patients (none with hemoglobinopathy) developed their autoantibodies in temporal association with alloimmunization after recent blood transfusion(s). CONCLUSION: RBC autoimmunization and the development of autoimmune hemolytic anemia should be recognized as a complication of allogeneic blood transfusion. The need for additional blood transfusion was successfully avoided in one patient by treatment with recombinant human EPO and corticosteroid therapy. Once RBC autoimmunization is identified, subsequent management should incorporate a strategy that minimizes subsequent exposure to allogeneic blood.