BACKGROUND AND PURPOSE: Bone morphogenetic proteins and their receptors are expressed in adult brains, and their expression levels increase after cerebral ischemia. The brain also expresses an inhibitor of bone morphogenetic protein signaling, noggin, but the role of noggin in ischemic disease outcome has not been studied. METHODS: We used transgenic mice overexpressing noggin to assess whether inhibition of bone morphogenetic protein signaling affects ischemic injury responses after permanent middle cerebral artery occlusion. RESULTS: Transgenic mice overexpressing noggin mice had significantly smaller infarct volumes and lower motor deficits compared to wild-type mice. CD11b(+) and IBA1(+) microglia along with oligodendroglial progenitors were significantly increased in transgenic mice overexpressing noggin mice at 14 days after permanent middle cerebral artery occlusion. CONCLUSIONS: These results provide genetic evidence that overexpression of noggin reduces ischemic brain injury after permanent middle cerebral artery occlusion via enhanced activation of microglia and oligodendrogenesis.