The neuropeptide α-melanocyte stimulating hormone (α-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central α-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-α and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of α-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central α-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central α-MSH. Intraperitoneal administration of the small dose of α-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central α-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central α-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by α-MSH could be used to treat systemic inflammation.