In order to examine the role of oxidative stress in asphyxia-induced perinatal brain damage, near-term fetal lambs were subjected to umbilical cord occlusion for approximately 60min until fetal arterial pH diminished to less than 6.9 and base excess to less than -20 meq/l. The levels of superoxide, hydrogen peroxide, glutathione (GSH) and thiobarbiturate-reactive substances (TBARS) within brain grey and white matter were determined at 72h to correlate with morphological changes. Although the topography and extent of brain damage varied somewhat from case to case, ranging from focal infarction in grey or white matter to subtle and patchy alterations of white matter, the telencephalic white matter appeared to bear the brunt of damage as compared to other regions. The parietal white matter, in particular was often the seat of early pathological changes that could be seen in isolation. These white matter changes were accompanied by significant increases in hydrogen peroxide and TBARS levels as compared to those in grey matter. In another set of experiments, 8 different brain regions were assayed for TBARS, GSH and superoxide dismutase (SOD). A highly significant rise in the levels of TBARS was again noted in the parietal and frontal white matter. SOD levels were higher in the frontal and parietal white matter, basal ganglia and cerebellum. Cerebral cortical and hippocampal neurons were relatively unaffected until accompanied by more severe damage to grey and white matter at other sites. These results suggest that the developing telencephalic white matter appears to be most vulnerable to the effects of intrauterine fetal asphyxia and that oxidative stress may be a major contributing factor in the pathogenesis of perinatal hypoxic-ischemic encephalopathy.