Background: Neonatal septicemia is widely recognized around the world. A prominent cause of infant mortality and morbidity. Folinolysis in sepsis causes a rise in the D-dimer marker, which is generated when cross-linked fibrin breaks down. Objective: The goal of this work was to evaluate the clinical significance of D-Dimer level for diagnosis of neonatal sepsis. Patients and Methods: Our study was done on 90 neonates divided into two groups: 45 septic neonates as cases and 45 healthy controls. A complete medical history, clinical examination, and diagnostic tests were performed for all newborns (CBC, CRP, blood culture, D-dimer). Results: Most of blood cultures were negative (42.2%) and the other positive cultures showed that klebsiella was the most common organism (22.2%), E-coli was 15.5%, Pseudomonas was 8.89%, Staph. Aureus was 6.67% and the less common was GBS (4.4%). CRP and D-dimer levels were significantly elevated in neonatal sepsis cases compared to controls. D-dimer at a cutoff point higher than 2 had 97.8% accuracy for detection of neonatal sepsis with 100.0% sensitivity and 95.6% specificity. D-dimer levels were significantly higher in infant sepsis patients who died compared to those who survived (5.5 ± 1.3 versus 3.2 ± 1.4) respectively indicating that D-dimer increased with increased severity of cases who had bad prognosis. Conclusion: D-dimer had 97.8% accuracy for detection of neonatal sepsis with 100.0% sensitivity and 95.6% specificity. So it may be used as a marker in neonatal sepsis.