Interleukin-1 (IL-1) receptor antagonist (IL-1ra) markedly reduces infarct volume induced by middle cerebral artery occlusion (MCAO) in the rat, when injected either centrally (intracerebroventricularly) or peripherally. The site or sites of action of IL-1 in stroke pathology, however, are not known. The present study investigated the site(s) of action of IL-1/IL-1ra in ischemic brain damage by studying the effects of local injection of IL-1ra into the cortex or striatum following permanent MCAO in the rat. Cortical injection of IL-1ra (5 micrograms) did not affect infarct volume in the cortex or striatum measured 24 h after MCAO. In contrast, striatal injection of IL-1ra ipsilateral to the infarction caused a significant and highly reproducible reduction of cortical (37%, p < 0.001) and striatal damage (27%, p < 0.001, corrected for edema) compared with vehicle-injected animals. Injection of IL-1ra (5 micrograms) into the striatum, contralateral to the infarction, resulted in a small (9%) but significant (p < 0.001) reduction of ipsilateral cortical damage, with no effect on ipsilateral striatal damage. Injection of a higher dose of IL-1ra (7.5 micrograms) in the contralateral striatum caused a further inhibition of ipsilateral cortical damage (24%, p < 0.001) and a significant reduction of ipsilateral striatal damage (16%, p < 0.001). In separate groups of rats, it was established that core temperature (measured continuously in free-moving animals with remote radiotelemetry) was not affected by striatal or cortical injection of IL-1ra. These data show that injection of IL-1ra into the striatum but not the cortex reduces infarct volume in both the striatum and the cortex, independently of effects on core temperature. These results imply that blocking striatal IL-1 contributes to IL-1ra-protective effects. We hypothesize that IL-1 may influence striatal distal cortical damage through either the release of specific substances or activation of polysynaptic pathways.