Investigations regarding hypertension and dietary sodium, both factors that influence stroke risk, have previously been limited to using genetically disparate treatment and control groups, namely the stroke-prone, spontaneously hypertensive rat and Wistar-Kyoto rat. In this investigation, we have characterized and compared cerebral vasoactive system adaptations following stroke in genetically identical, salt-induced hypertensive, and normotensive control mice. Briefly, ANP(+/-) (C57BJ/6 × SV129 background) mice were fed chow containing either 0.8% NaCl (NS) or 8.0% NaCl (HS) for 7 weeks. Transient cerebral ischemia was induced by middle cerebral artery occlusion (MCAO). Infarct volumes were measured 24-h post-reperfusion and the mRNA expression of five major vasoactive systems was characterized using qPCR. Along with previous publications, our data validate a salt-induced hypertensive state in ANP(+/-) mice fed HS chow as they displayed left ventricular hypertrophy, increased systolic blood pressure, and increased urinary sodium excretion. Following MCAO, mice fed HS exhibited larger infarct volumes than their dietary counterparts. In addition, significant up-regulation in Et-1 and Nos3 mRNA expression in response to salt and stroke suggests implications with increased cerebral damage in this group. In conclusion, our data demonstrate increased cerebral susceptibility to stroke in salt-induced hypertensive mice. More importantly, however, we have characterized a novel method of investigating hypertension and stroke with the use of genetically identical treatment and control groups. This is the first investigation in which genetic confounding variables have been eliminated.