OBJECTIVE Acute AMPK activation exacerbates ischemic brain damage experimentally.Paradoxically, the clinical use of an AMPK activator metformin reduces the incidence of stroke.We investigated whether post-stroke chronic metformin treatment promotes functional recovery and tissue repair via an M2-polarization mechanism following experimental stroke.METHODS Mice were randomly divided to receive metformin or vehicle daily beginning at 24 h after middle cerebral artery occlusion (MCAO).Neurological deficits were monitored for 30 d following MCAO.To characterize the polarization of the microglia and infiltrating macrophages, the expression of the M1 and M2 signature genes was analyzed with qPCR, ELISA and immunohistochemistry.Post-MCAO angiogenesis and neurogenesis were examined immunohisto-chemically.An in vitro angiogenesis model was employed to examine whether metformin promoted angiogenesis in a M2 polarization-dependent manner.RESULTS Poststroke chronic metformin treatment had no impact on acute infarction but enhanced cerebral AMPK activation, promoted functional recovery and skewed the microglia/macrophages toward an M2 phenotype following MCAO.Metformin also significantly increased angiogenesis and neurogenesis in the ischemic brain.Consistently, metformin-induced M2 polarization of BV2 microglial cells depended on AMPK activation in vitro.Furthermore, treatment of brain endothelial cells with conditioned media collected from metformin-polarized BV2 cells promoted angiogenesis in vitro.CONCLUSION Post-stroke chronic metformin treatment improved functional recovery following MCAO via AMPK-dependent M2 polarization.Modulation of microglia/macrophage polarization represents a novel therapeutic strategy for stroke.