The human autoimmune disorder systemic lupus erythematosus (SLE) is often accompanied by psychiatric manifestations including anxiety. In this study, the performance of SLE-prone NZB x NZW F1 (B/W) hybrid mice was compared with nonautoimmune NZW control mice on 3 anxiety tasks: the elevated plus maze, the open-field drink test, and the novel-object task. B/W mice displayed decreased activity as well as an anxiety profile in all 3 tasks, which was characterized by avoidance of open and exposed places even when the motivation to explore these areas was high. Cytokines are overexpressed in autoimmune disease, and NZW controls injected with the cytokine interferon-alpha displayed an anxiety profile in the plus maze. Thus, cytokines may play a role in the genesis of the behavioral manifestations of autoimmune disease.