Background and Purpose—We have recently demonstrated that pretreatment with magnesium (calcium and glutamate antagonist) and tirilazad (antioxidant) in combination with intraischemic mild hypothermia (33°C) (MTH) offers superior neuroprotective efficacy in a rat model of focal transient cerebral ischemia. In the present study, we investigated the time window of this treatment strategy with a posttreatment regimen to define its role for stroke patients.Methods—We subjected 48 Sprague-Dawley rats to 90 minutes of middle cerebral artery occlusion by an intraluminal filament. Bilateral regional cerebral blood flow was continuously recorded by laser Doppler flowmetry. Combination therapy with MTH was started at 0, 1, 3, and 5 hours after induction of ischemia. Drugs were given in 1-hour intervals, and hypothermia was maintained for 2 hours. Neurological deficits were assessed daily. Infarct size was planimetrically determined on postoperative day 7.Results—Combination therapy with MTH significantly reduced infarct volume compared with normothermic controls by −74%, −49%, and −45% when applied at 0, 1, and 3 hours after induction of ischemia. Furthermore, these treatment groups showed less neurological deficits on postischemic days 1 and 2 (P<0.05). Onset of treatment 5 hours after middle cerebral artery occlusion failed to significantly reduce infarct formation and neurological deficits.Conclusions—The therapeutic window of the new combination therapy is at least 3 hours after onset of ischemia, comparable to that of moderate hypothermia (30°C), a grade of hypothermia associated with higher risks of severe side effects.