This study aimed to characterise both neuronal autoantibodies and levels of IFNα, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). CSF and plasma from 35 SLE patients (15 with NPSLE) showed no antibodies against natively-expressed NMDA receptors, or the surface of live hippocampal neurons. By comparison to controls (n=104), SLE patient antibodies bound a peptide representing the extracellular domain of NMDARs (p<0.0001), however, binding was retained against rearranged peptides and no peptide (r=0.85 and r=0.79, respectively, p<0.0001). IFNα levels were higher in SLE (p<0.0001), without specificity for NPSLE. Neuronal-surface reactive autoantibodies are not detectable in NPSLE. Our findings mandate a search for novel biomarkers in this condition. This article is protected by copyright. All rights reserved.