Methyldopa therapy results in the formation of red cell autoantibodies in 10-20% of patients taking the drug for longer than 4 months. These red cell antibodies are true autoantibodies, that is they are directed against an autoantigen on the red blood cell membrane and not against the drug or against a drug-altered antigen. The target membrane antigen is usually within the Rhesus system, although often the antibody specificity cannot be defined. Red cell antibody is usually detectable in the patient's sera as well as on the red cells. The autoantibody is usually a warm reacting IgG antibody. Most patients who develop these autoantibodies do not go on to develop hemolytic anemia in spite of high titres of antibodies on their red cells. In addition, these patients do not tend to develop hemolysis if methyldopa therapy is continued. Rarely patients develop hemolytic anemia which can be severe. Differences in antibody characteristics, including subclass restriction, complement-binding ability, or titre do not explain why some patients with autoantibody hemolyze while most do not. One group of investigators found that hemolyzing patients had IgM on their red cells while those who did not had IgG only. But while this observation could explain why some patients (IgM-sensitized red cells) hemolyze, it does not explain why most patients with IgG-sensitized red cells do not hemolyze. Why the autoantibody forms is not known but some investigators have proposed that the drug may directly affect B or T cells with resulting impairment of immune tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)