Abstract Objectives: The study aimed to evaluate the discriminative ability of, at admission, estimation of serum high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and procalcitonin (PCT) between neonates with various grades of early-onset sepsis (EOS) using the Score for Neonatal Acute Physiology (SNAP II). Patients & Methods: The study included 87 neonates with suspected EOS within the 1st week of life. All neonates were evaluated using the SNAP II and scores >40 indicate severe, 20-40 indicate moderate and score <20 indicate mild infection. At admission, venous blood samples were obtained for blood culture, total (TLC) and differential leucocytic count and ELISA estimation of serum hsCRP, IL-6 and PCT.Results: EOS neonates were categorized as Confirmed (n=44), Suspected (n=18) and EOS-free (n=25) according to severity of clinical sepsis and result of blood culture. Estimated laboratory parameters were significantly higher in patients than controls and in EOS than EOS-free neonates. Serum hsCRP and IL-6 levels could not, while PCT could differentiate between neonates with confirmed or suspected EOS. ROC curve analysis defined high serum PCT and IL-6, SNAP II score, neutrophil percentages, serum hsCRP and TLC as significant predictors for positive blood culture in decreasing order of significance, while Regression analysis defined high serum PCT as a persistently significant predictor for positive culture, followed by high serum IL-6 and high SNAP II score. Combined SNAP II scoring and serum PCT could define 61.4%, while combined estimation of serum hsCRP, IL-6 and PCT levels could define 52.3% of neonates with combined EOS.  Conclusion: Combined estimation of hsCRP, IL-6 and PCT could increase the diagnostic yield of neonatal sepsis; however, clinical evaluation using SNAP II score and serum PCT did better and could define neonates with positive blood culture earlier so as to allow early treatment.