Neonatal environment can have important, life-long influences on stress-reactivity and hypothalamic-pituitary-adrenal (HPA) axis regulation. In rodents, brief mother-infant separations have been shown to improve efficiency of the HPA axis, decrease stress-reactivity, and decrease age-related declines in cognitive function. Here, we provide evidence that there are potential costs associated with improved HPA axis regulation, including increased sensitivity to cerebral inflammation and glucocorticoid-mediated neuronal death following stroke. Specifically, brief mother-infant separation decreases the initial corticosteroid response to experimental stroke in adult mice, but increases post-stroke pro-inflammatory cytokine expression, edema, and infarct volume compared to ischemic controls. Brief maternal separation also compromises functional recovery and long-term survival following stroke. In addition, adrenalectomy reverses the effects of brief maternal separation on stroke outcome when corticosterone is replaced at baseline, but not ischemic, concentrations; thus, neonatally separated mice are more sensitized as adults to the detrimental effects of elevated corticosterone during ischemia. Taken together, these data provide the first direct evidence that neonatal environment can substantially influence adult cerebrovascular health.