During cerebral reperfusion, the vasculature generates superoxide. Levels of superoxide dismutase (SOD) are low in the immature brain. SOD conjugated to polyethyleneglycol (PEG-SOD) enters endothelial cells without crossing the intact blood brain barrier. We used PEG-SOD to investigate how vascularly derived superoxide contributes towards the production of ischemic brain injury in the 7day old (P7) rat. P7 rats were injected with 30,000U /kg. of PEG-SOD i.p. Serum SOD levels peaked at 4hrs, t1/2= 25hrs. To determine a protective dose we produced a hypoxic-ischemic (HI) insult to the R cerebral hemisphere in P7 rats by R common carotid artery ligation followed by 2.25h exposure to 8% oxygen. We randomized rats (n=55) into 4 groups; Saline; PEG-SOD 10,000; 30,000 or 100,000 U/kg. All treatment was given i.p. 3h before hypoxia. At 42h after the HI insult we measured water content by the wet-dry method and calculated R hemisphere swelling: swelling was 21.8±8.8%(Mean±SD) for 15 saline treated and only 6.6±7.4 in the PEG-SOD 30,000 U/kg group, p=<0.0001 ANOVA. The 10,000 and 100,000 U/kg doses were not protective. Next we determined if treatment immediately after the HI insult could reduce brain injury so we repeated the HI insult and randomized rats (n=57) into 4 groups Saline, or PEG-SOD100,000; 60,000 or 30,000 U/kg i.p. At 42h recovery R hemisphere swelling was 21.9±9.7% (Mean±SD) in the 13 saline treated and 11.1 ±11.4 in the 60,000 U/kg and 6.4±5.6% in the 30,000 U/kg groups, p=0.003 and p=<0.0001 vs Saline respectively, ANOVA. To determine long term neuroprotection, 58 other rats were treated with Saline or 30,000 U/kg PEG SOD at 0 or at 1h of recovery from HI and allowed to recover 14 days when the brain was removed, fixed and 2mm coronal sections cut. We related the areas of the damaged right to the undamaged left hemispheres and found no long term protection compared to Saline, p=0.7, Kruskal-Wallis test. In a separate experiment, pretreatment(30,000u /kg i.p.) also did not protect against long term injury, p=0.7. In conclusion PEG SOD administered i.p. before or immediately after a HI insult in the P7 rat reduces brain swelling at 42h of recovery by 70% but it does not reduce long term brain atrophy.