Recent studies demonstrated that sulfonylurea receptor 1 (SUR 1) regulated nonselective cation channel, the NC(Ca-ATP) channel, is involved in brain injury in rodent models of stroke. Block of SUR 1 with sulfonylurea such as glibenclamide has been shown to be highly effective in reducing cerebral edema, infarct volume and mortality in adult rat models of ischemic stroke. In this study, we tested glibenclamide in both severe and moderate models of neonatal hypoxia-ischemia (HI) in postnatal day 10 Sprague-Dawley rat pups. A total of 150 pups were used in the present study. Pups were subjected to unilateral carotid artery ligation followed by 2.5 or 2 h of hypoxia in the severe and moderate HI models, respectively. In the severe HI model, glibenclamide, administered immediately after HI and on postoperative Day 1, was not effective in attenuating short-term effects (brain edema and infarct volume) or long-term effects (brain weight and neurological function) of neonatal HI. In the moderate HI model, when injected immediately after HI and on postoperative Day 1, glibenclamide at 0.01 mg/kg improved several neurological parameters at 3 weeks after HI. We conclude that glibenclamide provided some long-term neuroprotective effect after neonatal HI.