Spatial cognitive impairment is common after stroke insults. Voluntary exercise could improve the impaired spatial memory. Newly generated neurons in the dentate gyrus are necessary for the acquisition of new hippocampus-dependent memories. However, it is not well known whether voluntary exercise after stroke promotes neurogenesis in the adult dentate gyrus, thereby promoting spatial memory recovery. Here, we examined in mice subjected to focal cerebral ischemia the effect of voluntary or forced exercise on neurogenesis in the ischemic dentate gyrus and spatial memory. Exposure to voluntary wheel running after stroke enhanced newborn cell survival and up-regulated the phosphorylation of cAMP response element binding protein (CREB) in the dentate gyrus and reversed ischemia-induced spatial memory impairment. However, the enhanced newborn cell survival and CREB phosphorylation in the dentate gyrus and improved spatial memory were not observed in the mice exposed to forced swimming. Moreover, there was a significant correlation between the total number of surviving newborn cells in the dentate gyrus and the ability of mice to locate the platform in the Morris water maze. These results suggest that, in the adult mice, exposure to voluntary exercise after ischemic stroke may promote newborn cells survival in the dentate gyrus by up-regulating CREB phosphorylation and consequently restore impaired hippocampus-dependent memory. © 2007 Wiley-Liss, Inc.