Despite important progress in obstetric and neonatal care, Hypoxic-Ischemic Encephalopathy (HIE) is one of the common causes of neonatal brain damage. The aim of the present study was to investigate the possible neuroprotective effects of two different dosages of pentoxifylline (60 and 100 mg/kg) (PTX) on a model of perinatal HIE. Seven-day-old Wistar rat pups were subjected to right common carotid artery ligation and hypoxia (92% nitrogen and 8% oxygen) for 2h. They were treated with PTX or saline both immediately after hypoxia-ischemia (HI) and after 2h. In sham group animals, neither ligation, nor hypoxia was performed. Neuronal apoptosis was evaluated by the caspase-3 immunostaining methods. The numbers of caspase-3 immunoreactive cells in the parietal cortex and dentate gyrus were observed to have significantly increased in the HI, PTX60 and PTX100 groups compared to the sham group, and, no differences were detected between the HI, PTX60 and PTX100 groups. The numbers of caspase-3 immunoreactive cells in the cornu ammonis regions of the hippocampus were significantly higher in the HI, PTX60 and PTX100 groups than in the sham group. But, elevated in the PTX60 group was significantly lower than that determined in the HI group. However, the number of necrotic cells in all regions of brain were significantly lower PTX60 than HI and PTX100 groups. These results show that PTX administration after hypoxia-ischemia reduces neuronal apoptosis and necrosis. Therefore, PTX may be an effective drug to use to decrease the severity of neonatal hypoxic-ischemic brain injury.