Objective Neonatal sepsis is one of the most common causes for neonatal hospitalization in developing countries. It is also a major cause of mortality in the world affecting both developed and developing countries. Diagnosis and management of sepsis are a great challenge facing neonatologists in neonatal intensive care units due to nonspecific signs and symptoms. This study, therefore, was aimed to determine proportion and risk factors of neonatal sepsis at university of Gondar comprehensive specialized hospital, North West Ethiopia. Result Proportion of neonatal sepsis was 11.7%. Factors significantly associated with neonatal sepsis were: Neonatal related factors were: Premature rupture of membrane (AOR=2.74; 95%Cl (1.39, 5.38), congenital anomaly (AOR=3.14; 95%CI (1.09, 10.28), and low Apgar score (AOR=2.69; 95%Cl (1.37, 5.26). Maternal factors were: foul smelling vaginal discharge (AOR=2.75; 95%Cl (1.40, 5.38), and Intrapartum fever (AOR=3.35; 95%Cl (1.7, 6.62). In this finding proportion of Neonatal sepsis was low. Measures targeting the prevention of premature rupture of membranes and low Apgar score need to be taken, like strengthening maternal birth preparedness and complication readiness plans. Also, identification of congenital anomalies earlier in pregnancy may decrease neonatal sepsis.