Free iron chelation after hypoxia-ischemia can reduce free radical-induced damage to brain cell membranes and preserve electrical brain activity. We investigated whether chelation of free iron with deferoxamine (DFO) preserved cortical cell membrane activity of Na ϩ ,K ϩ -ATPase and electrocortical brain activity (ECBA) of newborn lambs during early reperfusion after severe hypoxia-ischemia. Hypoxia was induced in 16 lambs by decreasing the fraction of inspired oxygen to 0.07 for 30 min, followed by a 5-min period of hypotension (mean arterial blood pressure Ͻ35 mm Hg). ECBA (in microvolts) was measured using a cerebral function monitor. Immediately after hypoxia and additional ischemia, eight lambs received DFO (2.5 mg/kg, i.v.), and seven lambs received a placebo (PLAC). Two lambs underwent sham operation. One hundred eighty minutes after completion of hypoxia and ischemia, the brains were obtained and frozen. Na ϩ ,K ϩ -ATPase activity was measured in the P 2 fraction of cortical tissue. Na ϩ ,K ϩ -ATPase activity was 35.1 Ϯ 7.4, 42.0 Ϯ 7.6, and 40.7 Ϯ 1.4 mol inorganic phosphate/mg protein per hour in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p Ͻ 0.05: DFO versus PLAC). ECBA was 11.2 Ϯ 6.1, 14.8 Ϯ 4.8, and 17.5Ϯ.0.5 V in PLAC-treated, DFO-treated, and sham-operated lambs, respectively (p ϭ 0.06: DFO versus PLAC). Na Abbreviations DFO, deferoxamine ECBA, electrocortical brain activity PLAC, placebo Q car , carotid blood flow SHAM, sham-operated animals MRS, magnetic resonance spectroscopy P i , inorganic phosphate Hypoxia and ischemia during perinatal asphyxia give rise to an inadequate substrate supply to brain tissue, resulting in damage of neuronal cells. Although recovery of oxygenation and perfusion of the brain is mandatory to prevent further damage, reoxygenation of previously ischemic brain tissue has increasingly been recognized as an important mechanism for additional injury to the neuronal cells and the cerebral microcirculation (1, 2). Production of reactive oxygen species in the early reperfusion phase plays a substantial role in this type of brain cell damage: Reactive oxygen species such as superoxide and hydrogen peroxide can be converted into the highly reactive hydroxyl radical by transition metals, in particular free iron, ultimately leading to lipid peroxidation of the brain cell membrane and cellular damage (3). In recent experimental and clinical studies, we showed that chelation of free iron prevented posthypoxic-ischemic hypoperfusion and metabolic derangements of the brain and preserved ECBA (4, 5). We also found that the free iron chelator DFO effectively lowered free iron in cortical brain tissue (6).Inasmuch as the transmembrane enzyme Na ϩ ,K ϩ -ATPase is very susceptible to free radical-related lipid peroxidation (7, 8), we investigated in the present study whether DFO prevented free radical-induced alterations of the brain cell membrane after global hypoxia and ischemia, simulating severe birth