Background: The introduction of pathogens or conditionally pathogenic microorganisms into the bloodstream triggers a systemic inflammatory response syndrome known as sepsis. Objective: Comparison between Presepsin as well as procalcitonin in early diagnosis and prognosis of sepsis. Subjects and Methods: In a prospective cohort study that was done on 90 cases with early sepsis, who admitted to ICU at Tropical Medicine Department, Zagazig University Hospitals. On admission, levels of procalcitonin and presepsin were assessed as well as after twenty-four and seventy-two hours. Results: Regard cause of admission majority had confusion then drowsiness, regard sepsis causes majority had Urinary tract infection (UTI) then pneumonia. BCs, Cr, INR and CRP were significantly higher among +VE culture at all reading group but albumin at all reading, PLT in 2^nd and 3^rd reading and pH at all reading were significantly lower among -VE culture. Positive significant correlation was found between SIRS score and CRP at T0 and T2 and high significance at T1. CRP was highly significantly correlated with Modified SOFA score from T0 to T2. The correlation between SIRS score and procalcitonin was significant at T1 and T2. Procalcitonin was significantly correlated with Modified SOFA score at T1 and T2. Presepsin was significantly correlated with SIRS score from T0 to T2. The correlation between presepsin and Modified SOFA score was significant and highly significant at T1, T0 and T2 respectively. Conclusion: Similar to procalcitonin, presepsin shows promise as a marker to detect sepsis. Compared to procalcitonin, presepsin is a more reliable biomarker for early sepsis diagnosis.