Objective To investigate the effect of RNA interference targeting repulsive guidance molecule a (RGMa) on angiogenesis in rat cerebral cortex after focal cerebral ischemia/reperfusion (I/R) injury and its potential mechanism. Methods The experimental animals were randomly divided into sham operated group(S), cerebral I/R group, I/R plus RGMa-specific recombinant adenovirus (I/R+rAd-shRGMa) and I/R plus empty carrier recombinant adenovirus group (I/R+rAd-HK). Adenovirus were injected into the right cortex and hippocampus in rats before undergoing I/R surgery. The transient middle cerebral occlusion (tMCAO) model was induced by ligation with nylon monofilament. Location of RGMa and Neogenin was assessed by Laser confocal microscope 2 days after tMCAO. Seven days after adenovirus injection, the expression of CD31 was detected by immunohistochemistry and the expression of vascular endothelial growth factor a (VEGFa) was detected by Western blotting analysis. Neurological score was evaluated before animals were sacrificed. Results Both RGMa and Neogenin were expressed in CD31⁺ cells after focal cerebral I/R injury as shown by double staining. Suppression of RGMa via RNA interference increased the number of CD31⁺ cells and the expression of VEGFa, and improved the neurological deficits. Conclusion RGMa-targeted RNA interference can promote angiogenesis in peri-infarction cortex after cerebral I/R injury, which is partly related to the increase of VEGFa expression in the cerebral tissues.