This study was performed to determine the correlation between psychiatric manifestations and several autoantibodies that might participate in the pathogenesis of psychiatric disorders in the course of systemic lupus erythematosus (SLE). Fifty-one unselected outpatients with SLE were enrolled. Psychiatric evaluation was performed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. The prevalence of antibodies against endothelial cells (AECA), cardiolipin, beta2 glycoprotein I, Ro, Ro52, La, glial fibrillary acidic protein, ribosomal P protein, dsDNA, and nucleosomes was assessed by experimental and commercial enzyme-linked immunosorbent assays. According to the cutoff value, AECA were present in 11 of 17 (64.7%) SLE patients with psychosis and mood disorders and in 10 of 34 (29.4%) patients without psychiatric manifestations other than anxiety (P = 0.03). Moreover, the AECA binding index was significantly higher in the first group (P = 0.03). Conversely, no significant correlation was found between the presence of the other autoantibodies studied and psychiatric involvement. The results of this study suggest a relationship between AECA and psychosis and mood disorders in SLE, supporting the hypothesis of a biological origin of these disturbances.