Methyldopa can produce both a positive direct antiglobulin test and less commonly a positive indirect antiglobulin test. When the drug-induced antibody is present in the serum, it acts as a panagglutinin and reacts with all normal red blood cells; consequently crossmatch-compatible blood cannot be prepared. Although the methyldopa-induced antibody itself rarely produces hemolysis, difficulties can arise in previously unscreened patients in whom the panagglutinin may mask an unknown, pre-existing, and potentially hemolytic alloantibody. We report on our clinical and serologic management of 14 such patients for whom transfusions were requested.