Background and Purpose The efficacy of neuroprotective approaches in stroke may be influenced by existing comorbidities. Here, we compared the effects of normobaric hyperoxia (NBO) in normotensive versus hypertensive rats subjected to transient focal cerebral ischemia. Methods Male Sprague-Dawley and spontaneously hypertensive rats were subjected to transient focal ischemia via intraluminal filament occlusions of the middle cerebral artery. NBO was started 15 minutes after ischemic onset and stopped at the time of reperfusion. Acute neurological deficits and tetrazolium-stained infarct volumes were quantified at 24 hours. Results NBO reduced mean infarct volumes by approximate to 50% (P=0.0064) in normotensive Sprague-Dawley rats subjected to 100 minutes transient ischemia. No effects of NBO were observed in hypertensive spontaneously hypertensive rats subjected to either 100 minutes or 75 minutes of transient ischemia. No significant changes in neurological outcomes were detectable in any group. Conclusions NBO reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. These findings suggest that comorbidities may influence responses to potential treatments after stroke.