Interleukin-1beta (IL-1beta) has been implicated in ischemic brain damage. The site of action of IL-1beta in such damage is not known, but we have demonstrated previously that injection of the interleukin-1 receptor antagonist (IL-1ra) in the striatum but not the cortex of rats inhibits damage caused by permanent middle cerebral artery occlusion. The present study investigated the site of action of IL-1beta on ischemic damage by examining the effects of intracerebroventricular, striatal, or cortical injection of recombinant IL-1beta at the onset of permanent middle cerebral artery occlusion in the rat. Intracerebroventricular injection of IL-1beta (2.5 ng) significantly increased infarct volume in the striatum (35%, P < 0.0001) and in the cortex (44%, P < 0.0001) compared with vehicle treatment. Direct injection of IL-1beta into the striatum also increased infarct volume in both the striatum (36%, P < 0.0001) and the cortex (38%, P < 0.0001), whereas injection of IL-1beta into the cortex failed to affect infarct volume in either the striatum or the cortex. Cortical injection of a higher dose of IL-1beta (20 ng) also failed to affect ischemic damage in either the striatum or the cortex. Injection of IL-1beta into the striatum contralateral to the infarction had no effect on striatal damage in the ischemic hemisphere, but did increase cortical damage by 18% (P < 0.0001). In separate groups of animals, IL-1beta (2.5 ng) was injected into either the striatum or the cortex, and body temperature was recorded continuously in conscious free-moving animals by remote telemetry. Injection of IL-1beta at either site failed to influence body temperature, suggesting that exacerbation of brain damage by striatal injection of IL-1beta is not caused by effects on body temperature. These results imply that IL-1beta exacerbates ischemic damage by specific actions in the striatum where it can influence damage at distant sites in the cortex.