Autoantibodies which bind to integral membrane proteins of brain were tested for their ability to bind to cross-reactive antigens on non-neural tissue. Both brain specific autoantibodies and antibodies which bind to cross-reactive antigens were found. There were two types of brain reactive autoantibodies which could not be adsorbed by non-neural tissue. One type was adsorbable by crude cell membrane preparations of brain. The second type was reactive against integral membrane proteins of brain, but not adsorbable by any of the crude membrane preparations tested. Autoantibodies of the first type reacted against integral membrane proteins with apparent molecular weights of 75, 70, 62, 50, 27, 24 and 20 kDa, as determined by gel electrophoresis and immunoblotting. As in previous studies, a diversity of brain reactive autoantibodies were found. The greatest numbers and strongest banding patterns were seen in the autoimmune strains of mice. The non-autoimmune strain displayed these autoantibodies at much lower levels. These results are the first to find brain specific autoantibodies, from autoimmune mice, against integral brain membrane antigens. The data support the idea that there is a sub-population of brain reactive autoantibodies which are involved in the pathogenesis of neuropsychiatric manifestations in immunologic disorders, particularly systemic lupus erythematosus.