Interleukin-1β (IL-1β) is a cytokine released by activated macrophages and monocytes, which mediates many of the local and systemic responses to inflammation. Interleukin-1β induces anorexia in rats when administered peripherally or centrally. An endogenous antagonist for the IL-1 type I receptor has been characterized and cloned (IL-1ra). We have used this protein to ascertain the site of action for the anorexic effects of IL-1β. Male rats were food restricted and trained on an operant schedule for food reinforcement. Administration of recombinant human IL-1β (4 μg IP or 40 ng ICV) induced profound decreases in operant responding, with maximal effects 1–4 h post-injection. Interleukin-1ra pretreatment (2.4 mg IP or 24 μg ICV) completely blocked these effects when administered by the same route. In contrast, ICV IL-1ra only partially blocked the effects of IP IL-1β, and IP IL-1ra was unable to block the effects of ICV IL-1β. Interleukin-1ra did not affect responding by itself. These results suggest that IL-1β acts at both peripheral and central IL-1 receptors to reduce food-motivated behavior. To determine the central site of action of IL-1β, small quantities of IL-1β (5 and 30 ng) were infused into the ventromedial hypothalamus of male rats. Both doses produced profound decreases in responding; the magnitude and time course of these effects were nearly identical to those observed after ICV administration. These results suggest that the VMH may serve as a central site of action for the depressive effects of IL-1β on food intake. There is much controversy over the pathways of communication from the immune system to the brain. To test the hypothesis that the peripheral immune stimulus is transmitted to the brain via a neural communication pathway, mice were injected with lipopolysaccharide at a behaviorally active dose (10 μg IP). This treatment increased the concentrations of substance P, neurokinin A, and calcitonin gene-related peptide in mouse spinal cord in a prostaglandin-dependent manner. Maximal increases in neuropeptide content were observed 1 h post-injection. Finally, subdiaphragmatic vagotomy was found to attenuate the reduction in food-motivated behavior induced by both IL-1β and lipopolysaccharide in mice.