Interleukin-1 (IL-1) has been implicated in chronic and acute cerebral neuropathologies. IL-1 receptor antagonist (IL-1ra), a naturally occurring protein that binds to IL-1 receptors without inducing signal transduction, blocks several actions of IL-1. IL-1ra acts at the local level and it also circulates in the bloodstream. We now report evidence for a biological function of IL-1ra in the brain as an endogenous neuroprotective molecule. Cerebral expression of IL-1ra mRNA is induced rapidly by focal cerebral ischemia in rats, and inhibition of the action of IL-1ra, by passive immuno-neutralization, markedly enhances ischemic damage. To our knowledge this is the first report of an action of endogenous IL-1ra in the brain. Control of IL-1ra expression or action may therefore provide a useful therapeutic strategy to limit acute neurodegeneration.