Objective To establish the mouse model for application in the study of pathogenesis of EV71 infection and evaluation of vaccines or drugs. Methods A mouse-adapted strain MP10 was generated by a series of passages of the parental EV71 strain in the skeletal muscle of mice. And then the symptoms, virus replication and pathological changes of tissues of infected-mice were monitored. ResultsCompared to the parental strain, MP10 showed enhanced infectivity in RD cells and virulence in mice, and MP10 infection caused paralysis and death in 10-day-old mice. Skeletal muscle was the main site for virus replication and showed extensive necrotizing myositis, whereas no lesions were observed in neurological tissues. The muscles associated with respirometric activity showed severe necrosis, which might have caused the infected mice to experience difficulty in breath and was thought to be the cause of death. Conclusion The 10-day-old mouse model for lethal EV71 infection was established and it would be useful for vaccine and drug evaluation.