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OBJECTIVE: To investigate the therapeutic effect of hyperbaric oxygen (HBO) on experimental piglet hypoxic ischemic brain damage (HIBD) and its protective mechanism by using piglets as the animal model for HIBD in newborns. METHODS: Using Levine's method, thirty 7 day old HIBD piglets were randomly divided into the control group and the HBOtreated group in which the piglets were treated with HBO for 3 hours daily. Half of the piglets in each group were sacrificed on the 1st and 7th day after hypoxic ischemic (HI) injury respectively. For these two groups, we observed (1) the mortality and neurological symptoms; (2) the velocity of blood flow in the right carotid artery (rVCA); (3) the brain weight; (4) the quantitative analysis of subdiploid cells in the brain by flow cytometry. RESULTS: The mortality and the incidence of neurological symptoms in the HBO treated group were less than those in the control group (P<0.05). The brain weights in the two groups were not different significantly (P>0.05). The rVCA in the HBO treated group was faster significantly than that in the control group when the first HBO therapy ended ［(146.8±16.8) ml/min vs (123.9±27.6) ml/min］(P<0.01). The ratio of subdiploid cells to all cells in the HBO group was less than that in the control group in the bilateral hippocampus on the 1st and 7th day after HI, and in the left frontoparietal cortex on the 1st day after HI. CONCLUSIONS: HBO therapy is effective on HIBD, and should be recommended as a shortterm and early treatment.