Enterovirus 71 (EV71) is the major cause of hand, foot, and mouth disease which affects millions of children and claims hundreds of lives in China.Here we find that the NLRP3 inflammasome plays a protective role in mice after infected with EV71, as NLRP3 inflammasome components NLRP3, ASC or Caspase-1 deficient mice are susceptible to EV71 infection.At early infection stage, NLRP3 inflammasome deficient mice are unable to mount enough IL-1b and other inflammatory cytokines to control viral infection, whereas at later infection stage, uncontrolled virus infection in NLRP3 inflammasome deficient mice leads to severer necrotizing myositis and higher inflammatory cytokine production.