High-mobility group protein-1 (HMG-1 also termed HMGB-1), a DNA-binding protein, regulates gene transcription and stabilizes nucleosome formation. HMG-1 was recently implicated as a cytokine, because it is a late-acting mediator of endotoxin lethality that induces the release of pro-inflammatory cytokines from monocytes. Here it is shown that administration of HMG-1 into the cerebral ventricles decreases food intake (food intake=4.6g/mouse in controls vs 1.6g/mouse after 1 microg HMG-1 i.c.v.; P <0.05). Intracerebroventricular HMG-1 induced an increased in TNF and IL-6 expression in the brain, and mediated taste aversion with potencies equivalent to LPS. In a model of endotoxemia, passive immunization with anti-HMG-1 antibodies attenuated the development of hypophagia, indicating that HMG-1 is a mediator of sickness behaviour associated with endotoxemia.