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Respiratory syncytial virus (RSV) is the major cause of acute bronchiolitis in infants under 2 years old. Necroptosis has been implicated in the outcomes of respiratory virus infections. We report that RSV infection triggers necroptosis in primary mouse macrophages and human monocytes in a RIPK1-, RIPK3- and MLKL-dependent manner. Moreover, necroptosis pathways are harmful to RSV clearance from alveolar macrophages. Additionally, Ripk3 -/- mice were protected from RSV-induced weight loss and presented with reduced viral loads in the lungs.Alveolar macrophage depletion also protected mice from weight loss and decreased lung RSV virus load. Importantly, alveolar macrophage depletion abolished the upregulation of Ripk3 and Mlkl gene expression induced by RSV infection in the lung tissue.Autocrine tumor necrosis factor (TNF)-mediated RSV-triggered macrophage necroptosis and necroptosis pathways were also involved in TNF secretion even when macrophages were committed to cell death, which can worsen lung injury during RSV infection. In line, Tnfr1 -/- mice had a marked decrease in Ripk3 and Mlkl gene expression and a sharp reduction in the numbers of necrotic alveolar macrophages in the lungs. Finally, we provide evidence that elevated nasal levels of TNF are associated with disease severity in infants with RSV bronchiolitis.We propose that targeting TNF and/or the necroptotic machinery may be valuable therapeutic approaches to reduce the respiratory morbidity caused by RSV infection in young children., Competing Interests: Conflict of interest: L.D. Santos reports grants from CAPES, during the conduct of the study. Conflict of interest: K.H. Antunes has nothing to disclose. Conflict of interest: S.P. Muraro has nothing to disclose. Conflict of interest: G.F. de Souza has nothing to disclose. Conflict of interest: A.G. da Silva has nothing to disclose. Conflict of interest: J.S. Felipe has nothing to disclose. Conflict of interest: L.C. Zanetti has nothing to disclose. Conflict of interest: R.S. Czepielewski has nothing to disclose. Conflict of interest: K. Magnus has nothing to disclose. Conflict of interest: M. Scotta has nothing to disclose. Conflict of interest: R. Mattiello has nothing to disclose. Conflict of interest: F. Maito has nothing to disclose. Conflict of interest: A.P. Duarte de Souza has nothing to disclose. Conflict of interest: R. Weinlich has nothing to disclose. Conflict of interest: M.A.R. Vinolo has nothing to disclose. Conflict of interest: B.N. Porto reports grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), during the conduct of the study., (Copyright ©ERS 2021.)