Background: In spite of advancements in newborn care and maternal antibiotic prophylaxis for GBS, early-life sepsis caused by bacterial, viral, or fungal infections is still linked with significant mortality and long-term morbidity. In the first 72 hours of life, early onset neonatal sepsis (EOS) is a considerable source of disease and death. The C-reactive protein (CRP) test seems to be useful in baby septicemia. IL-27 is a heterodimeric cytokine generated by antigen-presenting cells in response to microbial products and inflammatory stimuli. It's said to have originated from the thymus. The purpose of this research was to assess the accuracy of interleukin 27 and C- reactive protein as early indicators for newborn sepsis diagnosis.. Methods: The research was done in neonatal intensive care unit (NICU), and was carried out on 100 newborns split into: Group I (cases): comprised 50 neonates with early onset neonatal sepsis admitted to NICU. Group II (control): contained 50 apparently healthy infants. All topics featured were submitted: Complete blood count (CBC) (CBC). C-reactive protein (CRP), Quantitative CRP and Interleukin 27. Results: The TLC of patients and controls did not change considerably. Median CRP was larger in cases (17) than controls (3), P=0.001. IL-27 levels were increased considerably in patients (773), compared to controls (129), P=0.001. . IL-27 exhibited a significant AUC of 0.856 (P-value <0.001) with a 95 percent confidence interval ranging from 0.783 to 0.929, demonstrating a good ability of diagnosis. The best cut-off point was > 195, with 90 percent sensitivity, specificity, PPV, and NPV. Conclusion: Interleukin 27 is a stronger early indication for neonatal sepsis than c- reactive protein .