Nervous system involvement in SLE encompasses a wide array of clinical manifestations which may reflect multiple etiologic factors including autoantibodies to nervous tissue antigens. The aim of the present study was to examine the association between autoantibodies to a wide range of brain antigens and cognitive abnormalities in an unselected population of 70 SLE patients. Using a battery of standardized neuropsychological tests, cognitive impairment was identified in 15/70 (21%) SLE patients compared with 1/25 (4%) patients with rheumatoid arthritis and 1/23 (4%) healthy subjects (P = 0.04). Integral membrane proteins were isolated from dissociated brain cells by temperature-induced phase separation with Triton X-114. Synaptosomes were isolated by differential centrifugation and membrane enriched fractions were prepared by lectin affinity chromatography. Western blotting identified IgG reactivity to a wide range of proteins (MW 22-52 K) in SLE patients. The proteins identified were distinct from well-characterized intracellular antigens including ribosomal P proteins. There was no significant difference in the prevalence of anti-brain antibodies between SLE patients who were cognitively impaired and those who were not impaired. Furthermore, there was no association between the presence of autoantibodies and subsets of cognitive dysfunction. These results suggest that circulating autoantibodies to brain antigens are not responsible for the abnormalities in cognitive function in SLE patients.