In response to infection or inflammation, individuals develop a set of symptoms referred to sickness behaviour which includes a decrease in food intake. The characterization of the molecular mechanisms underlying this hypophagia remains critical, since chronic anorexia may represent a significant health risk. Prostaglandins (PGs) constitute an important inflammatory mediator family which levels increase in the brain during inflammatory states and their involvement in inflammatory-induced anorexia was proposed. The microsomal prostaglandin E synthase-1 (mPGES-1) enzyme is involved in the last step of PGE2 biosynthesis and its expression is stimulated by pro-inflammatory agents. The present study attempted to determine whether an up-regulation of mPGES-1 gene expression may account for the immune-induced anorexic behaviour. We focused our study on mPGES-1 expression in the hypothalamus and the dorsal vagal complex, two structures strongly activated during peripheral inflammation and involved in the regulation of food intake. We showed that mPGES-1 gene expression was robustly up-regulated in these structures after intraperitoneal and intracerebroventricular injections of anorexigenic doses of IL-1. This increase was correlated with the onset of anorexia. The concomitant reduction in food intake and central mPGES-1 gene up-regulation led us to test the feeding behaviour of mice lacking mPGES-1 during inflammation. Interestingly, IL-1 failed to decrease food intake in mPGES-1 -/- mice although these animals developed anorexia in response to PGE2 injection. Altogether, our results demonstrate that mPGES-1, which is strongly up-regulated during inflammation in the central structures involved in feeding control, is essential for the immune anorexic behaviour and thus may constitute a potential therapeutic target.