OBJECTIVE: Our purpose was to study the neuroprotective effect of magnesium sulfate on hypoxic-ischemic brain damage and how the timing of magnesium administration changes its effect in the newborn rat. STUDY DESIGN: Seven-day-old rats (n = 91) were exposed to unilateral carotid artery ligation followed by 2 hours of hypoxia (8% oxygen in 92% nitrogen). Magnesium sulfate (270 mg/kg) was intraperitoneally administered 30 minutes before (pretreatment) or 30 minutes after (posttreatment) the 2 hours of hypoxia. In each experiment equivalent amounts of saline solution were administered as controls. Seven days after the injury the rats were killed and the brains were removed for histologic study with hematoxylin and eosin staining. The severity of brain atrophy and neuronal damage was evaluated in the cerebral cortex and hippocampus and compared by χ2 test between the magnesium group and the controls. RESULTS: ionized magnesium concentrations were significantly increased from 0.52 ± 0.02 mmol/L to 1.38 ± 0.07 mmol/L at 0.5 hour after injection and thereafter gradually decreased to 0.73 ± 0.07 mmol/L at 3.5 hours. Magnesium significantly reduced the incidence of weight loss (0% in magnesium vs 29% in controls) and protected the cerebral cortex from neuronal loss (the incidence of normal, mild, moderate, arid severe neuronal loss was 48%, 29%, 5%, and 19% in magnesium and 30%, 5%, 25%, and 40% in controls, respectively) in the pretreatment group. In the posttreatment group magnesium caused increased neuronal damage compared with the controls. CONCLUSION: Magnesium sulfate has neuroprotective effects against hypoxia-ischemia. This effect is restricted to the pretreatment group in which magnesium sulfate is administered before the insult.