Autoimmunity is considered the most likely cause of human narcolepsy-cataplexy, but no specific autoantibodies or antigen(s) have yet been identified. By means of indirect avidin-biotin immunohistochemical method, we searched for antibodies in serum from narcolepsy-cataplexy patients and controls that bind to rat hypocretin neurons. No staining was found in eight out of nine narcolepsy-cataplexy patients or controls. The serum from one narcolepsy-cataplexy patient, however, strongly produced staining of the membrane and superficial cytoplasm of neurons in the lateral hypothalamus. Dual staining revealed that the vast majority of the hypocretin-positive neurons were positive, but nonhypocretin neurons in the same area were binding antibodies from the patient's serum. These results show that antibodies bind to specific hypocretin- and nonhypocretin-containing neurons in the hypothalamus and indicate the presence of autoantibodies in narcolepsy patients.