Significance The CNS vasculature tightly regulates the passage of circulating molecules and leukocytes into the CNS. In the neuroinflammatory disease multiple sclerosis (MS), these regulatory mechanisms fail, and autoreactive T cells invade the CNS via blood vessels, leading to neurological deficits depending on where the lesions are located. The region-specific mechanisms directing the development of such lesions are not well understood. In this study, we investigated whether pericytes regulate CNS endothelial cell permissiveness toward leukocyte trafficking into the brain parenchyma. By using a pericyte-deficient mouse model, we show that intrinsic changes in the brain vasculature due to absence of pericytes facilitate the neuroinflammatory cascade and can influence the localization of the neuroinflammatory lesions.