The nonobese diabetic (NOD) mouse develops diabetes spontaneously due to autoimmune destruction of the pancreatic islets with a higher incidence in the female than the male. Prolactin (PRL), a hormone whose role has been previously focused on reproduction and lactation has been demonstrated to influence immune responses. In this study, we investigated the effect of hypoprolactinemia and hyperprolactinemia on the incidence of diabetes in male and female NOD mice. Our hypoprolactinemia model was induced from the time of weaning (21 days of age) to 112 days of age by daily injections of 200μmlg of bromocriptine (CB-154). A hyperprolactinemic model was induced by a syngeneic anterior pituitary transplant (APT) to the kidney capsule at 35 days of age and maintained until 112 days of age. Additional experimental groups were also investigated. A group of males received pituitary transplants combined with daily subcutaneous injections of CB-154. A group of females treated with CB-154 was also given daily subcutaneous injections of 30μmlg of oPRL. An ovariectomized (OVX-Control) group of females was also established to serve as a second control for the OVX-APT group. Bromocriptine administration did not significantly decrase plasma PRL levels compared to controls (CTRL) while APT animals had plasma PRL levels that were significantly higher (P0.0001). From these results we conclude that PRL can modulate the incidence of diabetes in NOD mice and hyperprolactinemia augments the autoimmune response leading to the development of diabetes.