Interferon regulatory factor-1 (IRF-1), a transcription factor that controls the expression of genes related to inflammation and injury, may be involved in the mechanisms of cerebral ischemia. In this study, we used immunohistochemistry to determine whether IRF-1 protein is up-regulated after cerebral ischemia, and to define the identity of the cells that express IRF-1 in the postischemic brain. In mice, IRF-1 immunoreactivity was present in intravascular neutrophils 24 h after middle cerebral artery occlusion. At 96 h, immunoreactivity was observed in neutrophils infiltrating the ischemic tissue and in neurons at the outer border of the ischemic territory. IRF-1 immunoreactivity was also found in neurons and inflammatory cells in the brain of patients who died 1-2 days after ischemic stroke. The neuronal expression of IRF-1, in conjunction with the finding that IRF-1 deletion is beneficial to the post-ischemic brain, suggests that expression of IRF-1-dependent genes in neurons plays a role in ischemic neuronal death.