We used Western blot analysis to examine the occurrence and titer of antibody to cytoskeletal neurofilament protein antigens in patients with neuropsychiatric manifestations of systemic lupus erythematosus (SLE) and in controls. Twenty-two patients with neuropsychiatric SLE (NPSLE) had an increased incidence of antineurofilament antibody (ANFA) compared with 34 patients with SLE without neuropsychiatric symptoms, 78 patients with other disease processes, and 22 healthy controls. ANFA were found to be directed against the 205,000- and 160,000-dalton proteins of the neurofilament triplet. Patients with a diffuse NPSLE clinical presentation had the greatest frequency of serum ANFA (7 of 12, 58%) compared with all other groups examined. Magnetic resonance imaging and serum anticardiolipin antibody testing were also performed in selected patients with NPSLE. Patients with a focal clinical presentation of NPSLE, positive magnetic resonance imaging findings, and negative serum ANFA had significantly elevated levels of anticardiolipin antibody.