Background: Hemodynamically significant patent ductus arteriosus (HSPDA) is associated with increased mortality and several significant morbidities including necrotizing enterocolitis (NEC), cerebral ischemia, intraventricular hemorrhage, pulmonary hemorrhage, or bronchopulmonary dysplasia. Objectives: The aim of the current work was to assess the cerebral hemodynamic changes and NEC in preterm infants diagnosed with HSPDA and to investigate the role of Human Epithelial derived neutrophil chemoattractant-78/ C-X-C Motif Chemokine Ligand 5 (ENA-78/CXCL5) as a diagnostic tool for NEC in HS PDA. Patients and Methods: This prospective case-control research was carried out on preterm infants (GA < 34 weeks) admitted at the Neonatal Intensive Care Unit, Benha University Hospitals, over one year from June 2021 till June 2022. Within 72 hours of birth, an echocardiographic examination was performed to check for a PDA. The included neonates were divided into three groups. 1st group was diagnosed with HSPDA, the second with non HSPDA, and the third with no PDA as control group. All newborns were exposed to full history taking, general and local examination, chest and abdominal radiographs, cranial ultrasound, and lab investigations in the form of CBC, electrolytes, and human (ENA-78/CXCL5) assay. Results: There was an increased incidence of cerebral ischemia, abnormal retrograde cerebral blood flow in anterior cerebral artery, intracranial hemorrhage, and periventricular leukomalacia (p-value <0.001, <0.001, <0.001, and 0.03 respectively) in hemodynamically significant PDA more than non-significant PDA and control group < strong>. Univariate logistic regression analysis showed that the left atria to aortic ratio and retrograde flow in descending aorta are significant and independent factors associated with cerebral ischemia, intracranial hemorrhage and hypotension. No variation in the incidence of NEC or mortality between the studied groups. Conclusion: It could be concluded that HSPDA is associated with higher incidence of cerebral complications. Human (ENA-78/CXCL5) had a role in the diagnosis of NEC in HS PDA.