Recent studies have suggested that hypothalamic and pituitary hormones may directly influence the immune system. One such hormone with immunomodulatory properties is GnRH. We hypothesized that GnRH and/or the gonadotropins might alter the severity of autoimmune disease through mechanisms distinct from their effects on gonadal hormones. This possibility was tested in a murine model of lupus. We assessed disease severity over time in intact and castrated, male and female, lupus-prone (SWR x NZB) F1 hybrid mice during treatment with GnRH agonist, GnRH antagonist, or vehicle. Compared to vehicle administration, GnRH antagonist administration significantly decreased total serum immunoglobulin G and anti-DNA antibodies in castrated male and female mice and significantly improved survival. In contrast, GnRH agonist administration exerted reciprocal effects in castrated mice, leading to early increases in serum anti-DNA and total immunoglobulin G levels. We conclude that GnRH and/or the gonadotropins can modify the expression of murine lupus independently of their regulation of gonadal steroid secretion.