Background: Neuron-Specific enolase is a dimeric isoform of the glycolytic enzyme that is mostly present in neurons is important as a diagnostic and a prognostic value in pediatric encephalopathy which is common and is potentially life threatening, previous studies were done worldwide to detect its diagnostic and prognostic value in acute encephalopathy among adult and pediatric age groups. Aim: Evaluation of serum Neuron Specific Enolase in pediatric patients with acute encephalopathy for early diagnosis of pediatric acute encephalopathy. Patients and methods: This case control study was carried out in Pediatric Intensive Care Unit and the inpatient pediatric department, Faculty of Medicine, Zagazig University and was conducted on 24 patients suffering from acute encephalopathy and 24 patients presented with seizures without encephalopathy. Serum Neuron-Specific Enolase was measured. Results: Serum Neuron-specific enolase level had sensitivity 95%, specificity 88.5%, PPV 94%, NPV 90% and accuracy 93% in prediction of encephalopathy. Conclusion: There was statistically significant increase in serum NSE levels in encephalopathy group more than seizures group