Literature in the immature animal indicates that the effect of mild to moderate hypothermia following an H-I insult is transient (Trescher et al, 1997), the protective effect being lost by 3-4 weeks of recovery. The objective of the present study was to determine, 1) the extent to which moderate vs severe H-I injury is ameliorated by post-ischemic hypothermia, and 2) the extent to which neuroprotective agents may be additive to the effects of post-ischemic hypothermia. To accomplish our first objective, 7-day postnatal rats were subjected to unilateral common carotid artery ligation and exposure to hypoxia in 8% oxygen while maintained at 37°C for periods of either 90 (moderate) or 180 (severe) minutes. Animals were then recovered for 3 hours in thermocontrolled waterbaths of 31, 34, or 37°C. Brains were examined neuropathologically at 7 or 21 days of recovery. At 7 days of recovery, only those animals which sustained a “moderate” H-I insult lasting 90 minutes, combined with post-ischemic hypothermia at 31°C displayed significantly less (p<0.05) brain damage then did their counterparts recovered at 34 or 37°C. By 21 days of recovery, this protective effect had dissipated. The findings indicate that post-ischemic mild hypothermia of 31°C can delay but not eliminate the extent of brain damage following a “moderate” (90 minute) H-I insult. Utilizing the results from our first investigation, 7-day rat pups were subjected to a moderate H-I insult at 37°C, afterwhich they immediately received subcutaneous injections of either, 1) 0.1 ml NS (control), 2) glutathione (1 mmol/kg), 3) N-acetylcysteine (6 mmol/kg), 4) flunarazine (30 mg/kg), 5) allopurinal (135 mg/kg), or 6) deferoxamine (100 mg/kg). Groups were then recovered at 31, 34, or 37°C for 3 hours, and then returned to their dams for neuropathologic assessment at 21 days of recovery. There was no difference in the extent of brain damage between control animals recovered at either 31, 34, or 37°C, confirming our earlier data. However, those animals receiving allopurinol combined with post-ischemic hypothermia of 31 or 34°C had significantly less (p<0.05) brain damage than did controls recovered at the same temperatures, as did those animals receiving glutathione in combination with hypothermia of 31°C during recovery. Thus, whereas mild post-ischemic hypothermia alone only delays brain damage following a moderate H-I insult, in combination therapy (allopurinol and glutathione) this important neuroprotective effect can be rendered permanent.