Background: Timely diagnosis of neonatal sepsis is critical. Early diagnosis of neonatal sepsis is still a great challenge. Objectives: To determine the significance of the hematological scoring system (HSS) for early detection of neonatal sepsis. Study design: A case control study done at the neonatal ICU, Al-Azhar Assiut university Hospital. It included sixty newborn infants divided into three groups (20 newborn infant for each one), septic, probably septic and control groups. Perinatal history with emphasis on risk factors for neonatal sepsis, Neonatal physical examination and laboratory investigation, including complete blood picture with differential, blood film, HSS (hematological scoring system) and blood culture. Results: HSS among septic group had a sensitivity (96%), specificity (90%), PPV (86.7%) and NPV (86%) and area under Receiver Operating Characteristic curve (ROC curve) with [95 % CI] was 0.76 (0.599 – 0.881).  Immature/total WBCs ratio had a sensitivity (80.3%), specificity (78.2%), PPV (66.3%) and NPV (84.7%) in early detection of neonatal sepsis. Immature/mature WBCs ratio had a sensitivity (78.3%), specificity (66.5%), PPV (42%) and NPV (60%) in early detection of neonatal sepsis. Total leukocytic count in the septic group was statistically significantly increased compared with the corresponding values in the probable septic and control groups (P= 0.021*). Conclusions: HSS is a useful test to distinguish the infected from non-infected infants. HSS is a simple, quick, readily available effective tool with high sensitivity and specificity in the early diagnosis of neonatal sepsis.