Background: When sepsis process starts, a variety of inflammatory cytokines pass into the circulation. These cytokines include tumor necrosis factor-α (TNF-α), leptin, interleukin-6 (IL-6, C-reactive protein (CRP) and procalcitonin (PCT). These cytokines are crucial inflammatory mediators. Measurement of the levels of inflammatory cytokines is an obvious marker for sepsis. Detectable serum cytokine levels can be obtained at a significant time before other laboratory indicators like leukocytosis or changes in absolute neutrophil count. This suggests their important role as diagnostic marker in sepsis. Objectives: To compare between sensitivity of serum leptin and C-reactive protein in early diagnosis of neonatal sepsis. Methodology: Prospective cohort study which carried out over 12 months from April 2017 to March 2018 at pediatrics department and Medical Microbiology and Immunology Department, Faculty of Medicine, Zagazig University. All neonates were subjected to complete history taking, detailed clinical examination, basic laboratory investigations which include (C-reactive protein), Complete blood picture, Bacteriological blood culture for isolation of the causative organisms and bacteria were identified by Vitec2, Serum leptin assay by sandwich enzyme-linked immunosorbent assay (ELISA). Results: 34 neonates that were classified regarding culture results into: Group 1 included newborns whose blood culture was negative. Group 2 included newborns whose blood culture was positive.76.5% of the studied group had positive blood culture results .There was statistical significance increase in WBCs, CRP 1st and CRP 2nd day among positive blood culture cases. There was statistical significance increase in Leptin among positive blood culture cases compared to negative blood culture cases. Conclusion: Leptin is a reliable diagnostic marker for neonatal sepsis and more accurate when compared with CRP.