In order to probe into dexamethasone's effect on glutamate receptor (Glu R) in hypoxic-ischemic encephalopathy (HIE) of newborn, we established newborn pigs' model of HIE to investigate Glu R in their forebrain crude synaptic membrane and the effect of dexamethasone in different HIE times and different dosages on the changes of Glu R. This study included five groups: HIE group (no medication); dexamethasone treatment group (10 mg/kg before HIE); dexamethasone treatment group (10 mg/kg after HIE); dexamethasone treatment group (5 mg/kg before HIE); dexamethasone treatment group (5 mg/kg after HIE). The results showed that the mean receptor density (Bmax) of dexamethasone treatment group (10 mg/kg before HIE) was significantly lower than that of the other groups (P < 0.05), but there was no statistic difference in the affinity of Glu R between all the experimental groups. These findings suggested that the preventive use of dexamethasone in large dosage would reduce the binding of Glu, and could possibly protect the brain tissues from damage in HIE.