The validity of the hypothesis that some of the neuropsychiatric manifestations of systemic lupus erythematosus (SLE) are mediated by the direct effects of antibody binding to neuronal cell membranes is dependent on the demonstration of antineuronal activity within the central nervous system of patients with active central nervous system disease. Using a radiolabelled staphylococcal protein A assay, we tested cerebrospinal fluid from 27 patients with SLE and central nervous system manifestations, and cerebrospinal fluid from 18 additional patients with SLE but free of central nervous system disease for antibody reactive with the cultured human neuronal cell line SK-N-SH. Cerebrospinal fluid from 20 of 27 patients with active lupus central nervous system disease had increased immunoglobulin G (IgG) antineuronal activity compared with cerebrospinal fluid from two of 18 patients with SLE without central nervous system disease. Ninety percent of the patients with psychosis, organic brain syndrome or generalized seizures had increased IgG antineuronal activity as compared with only 25 percent of the patients who presented with hemiparesis or with chorea/hemiballismus. Antineuronal activity per microgram of IgG was concentrated eightfold in the cerebrospinal fluid of patients with active central nervous system disease as compared with the serum activity. Patients with or without active central nervous system disease did not differ significantly in the amount of serum antineuronal binding activity. The results are consistent with the hypothesis that the more diffuse central nervous system manifestations of SLE are a direct result of the interaction of antibody with neuronal cell membranes.