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Influenza is an infectious disease caused by an RNA virus that affects birds and mammals. It is a leading cause of morbidity, mortality and economic loss worldwide. Under influenza A virus infection, an uncontrolled inflammatory response in the lungs frequently leads to severe pneumonia. The anti-inflammatory and immune modulatory effects of melatonin may provide a beneficial effect for this disease. In this study, we found that melatonin treatment significantly decreases the expression of TNF-α, IL-6 and IFN-γ, and increases the production of IL-10 and TGF-β. The induction of IL-10 by melatonin occurs via the upregulation of IL-27 expression in dendritic cells. Melatonin also significantly inhibits the production of TNF-α in CD8 T cells. Co-treatment of melatonin and ribavirin significantly increases the survival of virus-infected mice compared to ribavirin alone. Our study suggests that melatonin possesses a therapeutic potential in influenza-induced pneumonia as an adjuvant treatment with anti-viral drugs.