Autoantibodies to adrenal medulla that gave a diffuse immunofluorescent staining pattern were detected in 17 out of 107 (16%) patients with newly diagnosed Type I diabetes mellitus, in 13 out of 178 (7%) patients with long lasting disease but in none of 80 mixed control sera tested. The antibodies were of IgG class and 31 of the 33 positive sera also fixed complement. In 32 out of 34 cases, detection of the antibodies was correlated with the presence in the serum of pancreatic islet cell antibodies (ICA). The specificity of adrenal medullary antibodies is distinct from ICA and from C-cell antibodies since their reactivity was not abolished by preabsorption with extracts from human insulinoma or thyroid C-cell carcinoma. The presence in the serum of antibodies to adrenal medulla is not related to a functional defect of the adrenal medulla, but this new specificity indicates a further autoimmune reaction related to the natural history of Type I diabetes.