Using human neuroblastoma cell lines (IMR-6, NMB-7, SK-N-Mc, SK-N-SH) as sources, we characterized surface neuronal antigens as an initial step in determining the pathogenic role and clinical significance of neuronal antibodies in systemic lupus erythematosus (SLE) patients. SLE sera were screened for the presence of surface neuronal antibodies using a mixed hemadsorption assay. Thirty SLE sera were further tested by Western blotting and immunoprecipitation of lysed IMR-6 cells. Western blotting revealed binding to predominantly intracellular antigens, none of which was restricted to neuroblastoma cells. In contrast, immunoprecipitation experiments demonstrated binding to a 97K antigen, which appeared to be of surface origin, by 3 SLE sera. This was not present on non-neuronal cells and was not precipitated by sera from healthy or disease controls. This 97K antigen was also precipitated from the neuroblastoma cell line NMB-7, but was not present on SK-N-Mc or SK-N-SH cells. Precipitation was depleted by preabsorption with viable IMR-6 and NMB-7 cells, but not with non-neuronal cells. Thus, some SLE sera recognize a 97K neuronal antigen on select neuroblastoma cells.