Peptide histidine isoleucine (PHI) and VIP are derived from the same precursor. While central VIP decreases food intake, potential effects of PHI on feeding have not been studied. In the current study, we found that PHI administered intracerebroventricularly (ICV) or into the hypothalamic paraventricular nucleus (PVN) or central nucleus of the amygdala (CeA) decreased food consumption in overnight-deprived rats. The magnitude of an anorexigenic response to PHI differed depending on the injection route: ICV-infused peptide evoked the most potent effect. We determined that that only PVN- and CeA-injected PHI did not have aversive consequences. In addition, we infused anorexigenic doses of PHI via the same routes and assessed Fos immunoreactivity of PVN oxytocin (OT) and vasopressin (VP) neurons using double immunohistochemistry. OT and VP are thought to promote feeding termination. PHI increased the percentage of Fos-positive OT neurons regardless of the injection route. PVN- and ICV-infused PHI induced activation of VP cells. We conclude that central PHI has an inhibitory influence on food intake in rats. The PVN, with OT and VP neurons, and CeA may be involved in the mediation of anorexigenic effects of PHI.