Platelet activating factor (PAF) is an inflammatory lipid mediator released by ischemic brain. The objectives of this study were to investigate the role of PAF in a neonatal model of hypoxic-ischemic (HI) brain injury. We produced a hypoxic-ischemic insult to the R cerebral hemisphere of 7day old rats by R common carotid artery ligation and exposure to 8% oxygen for 2.25h. Using a biological assay, we measured PAF activity in brain homogenate obtained from groups of 7day old rats (n=4-7) killed at 0,2,6,24, and 48h of recovery from HI. To determine if inhibition of PAF before the HI insult would be protective, 42 rats received either saline or 10mg/kg s.c. of PAF antagonist WEB2170, 1h before hypoxia. At 42h of recovery the rats were killed and hemisphere water content measured (wet- dry wt). R Hemisphere (RH) swelling was calculated. Other rats n=59, were similarly treated before the HI insult but allowed to recover 14 days when the hemispheres were dissected and weighed. The% RH atrophy was calculated by the formula: (LHwt - RHwt)/LHwt×100. In other rats we administered WEB2170 (1 or 10mg/kg s.c.) at the onset of recovery from the HI insult and measured RH swelling at 42h of recovery. PAF activity was 563 ±379pg/0.3g wet brain wt (Mean±SD) in 8 normal brain homogenates. PAF activity in the LH and RH was similar. It did not change during 48h recovery. In the pretreatment study the RH of the 22 saline treated rats swelled 13.9±9.0% (Mean±SD) while in the 20 WEB2170 treated rats it swelled only 6.3±8.7%,P=0.003, Mann-Whitney U test. RH atrophy at 14d recovery was 21.16±16.16% in the 27 saline treated and 20.9±16.7% in the 32 WEB2170 treated, p=.99 Mann-Whitney U test. When WEB2170 was given in doses of 1mg and 10mg/kg vs saline (n=15 per group), immediately upon recovery from hypoxia no reduction in brain swelling was achieved, p=.96 Kruskal- Wallis Test. In conclusion inhibition of PAF with a single dose of WEB2170 before cerebral hypoxia-ischemia in 7day old rats reduced brain swelling at 42h of recovery but did not reduce brain atrophy at 14d recovery.