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RNA interference (RNAi) functions as a potent antiviral immunity in plants and invertebrates; however, whether RNAi plays antiviral roles in mammals remains unclear. Here, using human enterovirus 71 (HEV71) as a model, we showed HEV71 3A protein as an authentic viral suppressor of RNAi during viral infection. When the 3A-mediated RNAi suppression was impaired, the mutant HEV71 readily triggered the production of abundant HEV71-derived small RNAs with canonical siRNA properties in cells and mice. These virus-derived siRNAs were produced from viral dsRNA replicative intermediates in a Dicer-dependent manner and loaded into AGO, and they were fully active in degrading cognate viral RNAs. Recombinant HEV71 deficient in 3A-mediated RNAi suppression was significantly restricted in human somatic cells and mice, whereas Dicer deficiency rescued HEV71 infection independently of type I interferon response. Thus, RNAi can function as an antiviral immunity, which is induced and suppressed by a human virus, in mammals.Human enterovirus 71 (HEV71) protein 3A is a viral suppressor of RNAi (VSR)VSR-deficient HEV71 induces viral siRNA production in somatic cells and miceHEV71-derived siRNAs load into AGO and degrade cognate HEV71 RNAThe replication defects of VSR-deficient HEV71 can be rescued by Dicer deficiencyIt remains unclear if RNAi is an antiviral immunity in mammals. Qiu et al. demonstrate that a human enterovirus deficient in the RNAi suppression activity of 3A protein triggers virus-derived siRNA production, and this virus-induced RNAi response indeed plays antiviral roles in human somatic cells and mice.