Free radical inhibitors have shown promise in several hypoxic ischemic brain injury models, and we wished to see if this work could be extended to our newborn piglet model using U-74389G, a 21-aminosteroid free radical inhibitor. Methods: Forty-four 0 to 3 day old piglets had carotid snares and arterial and venous catheters placed under 1.5% Isoflurane anesthesia. While paralyzed with Succinylcholine under 0.5% Isoflurane, 50% Nitrous Oxide, they were randomly assigned to receive either 3 mg/kg of U-74389G or vehicle at time -15 minutes and again at 90 minutes. At time 0, both carotid arteries were clamped and blood was withdrawn to reduce the blood pressure to two-thirds normal. At time 15 minutes inspired oxygen was reduced to 6%. At time 30 minutes the carotid snares were released, the withdrawn blood was reinfused, and the oxygen was switched to 100%. On the third day after the hypoxic ischemic injury, the animals were killed by perfusing their brains with 10% formalin. Neurologic examination and brain pathology were scored by blinded observers. A subset of 5 piglets in each group had their brains frozen in liquid N2 at 15 minutes after reoxygenation, removed, and assayed for malonaldehyde (MDA). 5 sham piglets were also assayed for MDA. Results: Neurologic exam at 24 hours after injury was 9.25 in both groups. (20 is normal, 5 is brain dead). Pathologic examination scores in the piglets surviving the full three days were 19.5 [11.5, 24.5] (median [25%, 75%]) in the control group and 18.5 [6.5, 29] in the U-74389G group. (30 is normal, 3 is total necrosis, p=ns). MDA levels were 526 ± 205 pMol/g in the shams, 338 ± 180 in the hypoxic ischemic controls, and 500 ± 157 in the U-74389G groups (p=ns). Conclusions: The 21-aminosteroid U-74389G when given at a dose of 3 mg/kg prior to injury and 1 hour after injury does not affect the severity of hypoxic ischemic brain injury in the newborn piglet. Free radicals are not increased by hypoxic ischemic brain injury in this model.