Recent evidence suggests that the peptide hormone prolactin (PRL) modulates energy balance through a number of mechanisms including acting in the brain to increase food intake. In the current studies we first demonstrated that chronic infusions of PRL into the lateral ventricles increased food intake in cycling rats without disrupting estrous cyclicity. In subsequent experiments the hypothesis that at least part of PRL's ability to increase food intake resulted from PRL-induced leptin resistance was tested. Female rats given chronic infusions of PRL (5µg/hr) into the cerebral ventricles for 10 days did not show a reduction in food intake or body weight following a central injection of 4µg murine leptin whereas the expected reduction in both of these parameters was seen in vehicle-infused rats. Leptin injections were without effect on these parameters whether they were administered to free feeding prolactin-infused rats or following 24h food deprivation. This lack of a behavioral response to leptin was accompanied by an attenuation in Fos induction and phosphorylation of STAT3 following leptin administration in PRL-infused rats in both the VMH and PVN.