A high frequency of autoantibodies to brain proteins has been reported in HIV-1-positive patients. However, the specificity of this response has not been characterized. Using homogenized tissue from three normal brains, the presence of autoantibodies to human brain proteins was analyzed in 16 HIV-1-positive patients with AIDS dementia complex (ADC), 10 HIV-1-positive patients without ADC, 10 patients with multiple sclerosis, 10 patients with juvenile rheumatoid arthritis, and 10 normal controls. Although antibodies to various brain proteins were detected in sera from one-third HIV-1-infected individuals with or without ADC, the proteins recognized were different among different brains. Only one ADC patient had consistent seroreactivity to a 50-kDa brain-specific protein. Our results indicate that autoantibodies to brain proteins are infrequently present in patients with ADC.