Vascular endothelial growth factor-B (VegfB) is an angiogenic protein related to VegfA, although it acts on a different set of tyrosine kinase receptors. Like VegfA, VegfB is expressed in the brain and is induced at sites of brain injury. VegfA has neuroprotective and angiogenic effects, but VegfA-knockout mice die in utero, so the effect of endogenous VegfA signaling in neuropathologic states, such as cerebral ischemia, cannot be tested directly. In contrast, VegfB-knockout mice survive to adulthood with little abnormality in the absence of pathologic stresses. To determine if VegfB regulates the severity of cerebral ischemia, the middle cerebral artery was occluded in VegfB-knockout, heterozygous, and wild-type mice, and the volume of the resulting cerebral infarcts and associated impairment of neurologic function were measured. Infarct volume was increased by approximately 40% and neurologic impairment was more severe in VegfB-knockout mice, implying that endogenous VegfB acts to protect the brain from ischemic injury. VegfB also protected cultured cerebral cortical neurons from hypoxic injury, suggesting that its protective action is mediated at least in part through a direct effect on neurons.