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Abstract: Neuroglobin (Ngb), a newly identified globin in vertebrate brain, has been suggested to be able to protect against brain hypoxic–ischemic injury. However, owing to its large size, the impermeability of the blood–brain barrier (BBB) to Ngb limits its application in brain injury. Recently, the 11-amino-acid human immunodeficiency virus trans-activator of transcription (TAT) protein transduction domain was shown to successfully deliver macromolecules into the brain. This study explored whether the TAT–Ngb fusion protein can cross the BBB and protect the brain from cerebral ischemia. The TAT–Ngb fusion protein generated from Escherichia coli BL21 (DE3) was efficiently delivered into mice brain tissues by intravenous injection as demonstrated by immunohistochemistry and Western blotting. Two groups of mice were treated with filamentous middle cerebral artery occlusion (MCAO) for 30min or 2h followed by reperfusion. Each group was then divided into sub-groups and was injected intravenously with TAT–Ngb, Ngb, or saline respectively before MCAO or immediately after reperfusion. Compared with the Ngb- and saline-treated group, the group with TAT–Ngb treated 2h before MCAO showed significantly less brain infarct volume and had better neurologic outcomes (p <0.05). Furthermore, a TAT–Ngb injection following a 30-min MCAO treatment significantly increased neuronal survival in the striatum (p <0.05). Our results demonstrated that the exogenous Ngb fusion protein containing the TAT protein transduction domain could be efficiently transduced into neurons in the mouse and protect the brain from mild or moderate ischemic injury. [ABSTRACT FROM AUTHOR]