We investigated the presence of cell-mediated immunity to neural antigen in diabetes mellitus. The lymphocytes were tested for sensitization to purified antigens of the central and peripheral nervous systems by measuring specific transformation in vitro. The antigens used were a CNS basic encephalitogenic protein and P2, a peripheral nerve basic protein. Of the 40 insulin-requiring diabetes patients, 24 showed clinical manifestations of diabetic neuropathy, and the 16 patients without neuropathy served as a control group. Of the 24 neuropathic patients, 15 showed a positive lymphocyte stimulation index to either one or both antigens, whereas of the 16 control patients only one showed a positive index, and to the P2 antigen only. These findings suggest that cell-mediated autoimmunity may play a role in the pathogenesis of diabetic neuropathy.