Prolactin, an anterior pituitary hormone, stimulates humoral and cell-mediated immunity. This study investigated effects of manipulating prolactin levels in the autoimmune B/W mouse model of SLE. A group of B/W females was treated with daily injections of the prolactin-suppressing drug, bromocriptine. These mice had delayed elevation of anti-DNA antibodies and serum IgG; longevity was increased compared to control mice. Functioning syngeneic pituitary glands, implanted under the renal capsule, produced prolonged hyperprolactinemia in a separate group of female B/W mice. Hyperprolactinemic animals were characterized by premature albuminuria, elevated circulating gp70IC and IgG, and accelerated mortality. Analyses of thymic and splenic lymphocytes revealed no differences in lymphocyte subpopulations in mice with altered prolactin levels. This is the first report to substantiate an immunomodulatory role for prolactin in B/W mice. Further evaluation of this model may identify specific means of intervening clinically with immunosuppressive hormone-modulating therapy in SLE.