The objective of this study is to investigate the presence of autoantibodies cross-reacting with the NR2 subunit of the N-methyl-d-aspartate (NMDA) glutamate receptor in plasma samples of patients with systemic lupus erythematosus (SLE), in their healthy first-degree relatives and in healthy unrelated individuals and to determine whether these autoantibodies are specific for lupus patients in general or for the subgroup of SLE patients with neuropsychiatric (NP) manifestations. Plasma samples were collected from 51 lupus patients (19 with and 32 without NP manifestations), 161 first-degree relatives and 55 healthy unrelated controls. Antibodies to a linear peptide of the NR2 subunit of the NMDA receptor were determined by enzyme-linked immunosorbent assay. A significant difference in mean antibody reactivity between SLE patients and healthy unrelated controls (P < 0.01) and between firstdegree relatives and healthy unrelated controls (P < 0.001) was found. No difference was found between lupus patients and their first-degree relatives or between lupus patients with and without NP symptoms. In this study, anti-NMDA receptor autoantibodies show more specificity for lupus patients (but not for selected patients with NP symptoms) and their first-degree relatives than for healthy controls, indicating a familial basis to mount an immune response to this peptide. Lupus (2007) 16, 329—334.