Pretreatment with the synthetic glucocorticoid dexamethasone prevents hypoxic-ischemic brain damage in 7-day-old neonatal rats. We presently characterize the response further by examining the effect of varying the age, the glucocorticoid, and the time of injection and by examining whether fasting can influence the response. Rats (n = 193) were randomized to one of 16 different treatment groups and subjected to hypoxia-ischemia (right carotid artery occlusion +8% O2 which was 3 h in duration for 7-day, 1 h for 2-week, and 30 min for 1-month-old animals). The brains were subsequently perfusion fixed and the area of infarction was measured from hematoxylin- and eosin-stained sections. Time dependence studies demonstrated that treatment with 0.1 mg/kg intraperitoneal dexamethasone 4 h prior to hypoxia reduced infarct size compared to vehicle-treated animals whereas pretreatment at either 48 h or 4 days was ineffective. Dexamethasone pretreatment (4 h) also provided neuroprotection against 4 h of hypoxia-ischemia. Fasted animals which received dexamethasone had reduced blood glucose levels yet markedly less damage than controls. Another glucocorticoid, methylprednisolone (0.7 mg/kg), also reduced infarction. In 2-week-old animals the area of infarction was reduced by pretreatment with dexamethasone, whereas in 1-month-old animals dexamethasone was ineffective. The results suggest that a glucocorticoid-mediated response intervenes in events leading to neuronal death in young animals but not older animals once myelination and synaptogenesis are complete.