BACKGROUND: Neonatal encephalopathy is a heterogeneous syndrome characterised by signs of central nervous system dysfunction in the newborn. Matrix metalloproteinase-9(MMP-9) increases the blood-brain barrier permeability, and their inhibitors can reduce its damage. MMP-9 has been implicated specifically in cerebral ischemia. AIM: To measure serum MMP-9 in neonatal hypoxic-ischemic encephalopathy and evaluate its correlation to the severity of early prediction and treatment. METHODS: its case-control study. The serum concentration of MMP-9 was determined by ELISA in 100 hypoxic neonates and 50 healthy neonates of matched age and sex who served as controls. RESULTS: In our present study the serum MMP-9 level was significantly higher at p = 0.0001 in hypoxic-ischemic full-term newborns (176.7 ± 68.7 ng/ml)as compared to control newborn (69.4 ± 34.85 ng/ml)and it was significantly higher at p = 0.0075 in hypoxic-ischemic preterm newborn (171.2 ± 132.9 ng/ml) when compared to control newborn (72.54 ± 36.74 ng/ml),also MMP-9 was significantly higher at Sarnat stage III at p = 0.0001. CONCLUSION: Serum MMP-9 level was significantly higher in hypoxic-ischemic newborns, and significantly increased with severity, so we suggest that serum MMP-9 level is important for predicting neurological sequel and severity in neonatal encephalopathy.