Abstract. OBJECTIVE: The objective of this study is to evaluate the therapeutic efficacy of melatonin as an adjuvant therapy in treating neonatal sepsis. PATIENTS AND METHODS: A prospective clinical trial study was conducted on 50 infants with neonatal sepsis diagnosed on the basis of both clinical and laboratory criteria. Enrolled infants were divided into two groups. Intervention group (n = 25) received melatonin and antibiotics, while the control group (n = 25) was treated with antibiotics only. Melatonin was administered as a single oral dose of 20 mg and antibiotics were administered according to a standard protocol. Both groups were compared using a predefined sepsis score utilizing both clinical and laboratory parameters. RESULTS: There was no significant difference in sepsis score between both groups before starting melatonin (p -value = 0.99), while there was significant difference in sepsis score between groups after 24 hours, 48 hours and 72 hours of starting melatonin with (p -value = 0.008, 0.006 and 0.002, respectively). There was significant improvement sepsis score in both groups with more improvement of sepsis score in the intervention group. CONCLUSION: Administration of melatonin as an adjuvant therapy in the treatment of neonatal sepsis is associated with improvement of clinical and laboratory outcomes.