BACKGROUND: The aim of this study was to determine the effect of vagus nerve stimulation (VNS) on infarct size after transient and after permanent focal cerebral ischemia in rats and to test the hypothesis that VNS-induced neuroprotection is due to changes in cerebral blood flow. METHODS: Ischemia was produced by either temporary proximal middle cerebral artery occlusion (TMCAO) or permanent distal middle cerebral artery occlusion (PMCAO). Stimulating electrodes were implanted on the cervical part of the right vagus nerve, and electrical stimulation was initiated 30 minutes after the induction of ischemia and delivered for 30 seconds every 5 minutes for 1 hour. All the procedures were duplicated but no stimulus was delivered in control groups. Cerebral blood flow in the MCA territory was continuously monitored with laser speckle contrast imaging. A neurologic evaluation was undertaken after 24 hours of ischemia, and animals were euthanized and neuronal damage evaluated. RESULTS: Ischemic lesion volume was smaller in VNS-treated animals in both the temporary and permanent ischemic groups (P<.01). VNS-treated animals in TMCAO had better functional scores at 24 hours as compared with control animals (P<.01), but there were no statistically significant differences in the neurobehavioral scores in PMCAO (P=.089). Cerebral blood flow changes in the MCA territory during ischemia did not differ between the VNS-treated animals and control animals in either group. CONCLUSIONS: VNS offers neuroprotection against stroke in both temporary and permanent ischemia. Although the precise mechanism of this effect remains to be determined, alterations in cerebral blood flow do not appear to play a role. VNS could readily be translated to clinical practice.