Introduction: Pro inflammatory cytokines are important mediators causing brain injury in neonates with H.I.E. Objective: This work aims to test the hypothesis that an anti-inflammatory agent (Ibuprofen) can ameliorate the brain injury in HIE and improve neuro-developmental out come when given to term infants immediately after the insult. Patients and methods: 40 asphyxiated term infants were assigned to one of two subgroups: Intervention and non-interventions; the intervention subgroup received 3 doses of oral Ibuprofen (10mg\kg at 6hrs postnatal then 5mg\kg at 24 and 48 hrs). 20 full term healthy neonates of matched age, sex and weight were served as control. Urinary PGE2 was measured at enrollment and after administration of last dose of the drug. Serial cranial sonar, clinical and neurological evaluation and developmental screening were performed. Results: Intervention and non-intervention subgroups did not differ regarding the severity of HIE at enrollment nor the incidence of neurological abnormalities at hospital discharge. The mean urinary PGE2 level was statistically significantly higher in asphyxia group compared to control group. Within the asphyxia group, there was statistically significant difference between grade II and grade III HIE regarding the mean of initial urinary PGE2 level where it was higher in grade III. Meanwhile, there was statistically significant deference between the two grades of HIE regarding the mean urinary PGE2 after the last drug dose within the intervention subgroup where it was 1.31 pg/ml 1.018 in grade II versus 4.37 pg/ml 2.07 in grade III. The results of the present study confirm the ability of neurosonography to identify wide variety of parenchymal abnormalities. As regards timing of events, earliest son graphic abnormalities to be observed were diffuse parenchymal echoes or slit like ventricles. Focal and periventricular echo dense lesion made their first appearance on day 3 of life. Interestingly, pattern and severity of son graphic findings was directly related to the severity of hypoxic injury. In striking contrast none of the patients with severe HIE (stage ш) had normal scans. While focal parenchymal or periventricular lesions characterized severe HIE, slit like ventricles were the predominant neurosonographic abnormality in stage II HIE. Conclusion: Although level of PGE2 decreases by administration of oral Ibuprofen in grade II HIE yet early administration of the drug did not affect out comes in infants with perinatal asphyxia. This may be explained by ineffectiveness in blocking inflammatory cytokines, if dose and route of administration were inadequate, or if other mediators existed that could have a more powerful role in brain injury during hypoxia-ischemia.