Objective To explore the risk factors associated with death cases of hand-foot-mouth disease(HFMD) in Hubei Province 2010-2012,so as to provide a scientific evidence for its prevention and control. Methods The 63 death cases of HFMD between 2010 and 2012 in Hubei Province were selected as case group,and the 189 survival cases of serious HFMD,which were randomly selected with a ratio at 3∶1 in the same period in Hubei as control group.The basic information,hospitalized experience,clinical symptoms and laboratory test results had been surveyed and the relevant risk factors were analyzed by single factor and multi-factor Logistic regression. Results The results of single-factor Logistic regression indicated that diagnosis of HFMD in the first visit to hospital and rash were two protective factors.While age less than 1 year old,living in rural areas,breastfeed,rural clinics and township medical institutions as the first choice,medication of hormone,medication of antibiotics and EV71 infection were nine risk factors.The results of multi-factors Logistic regression showed that diagnosis of HFMD in the first visit to hospital(OR=0.276,95%CI:0.082~0.937)were protective factors of death of HFMD.Age less than 1 year old(OR=8.222,95%CI:1.875~36.046),living in rural areas(OR=3.459,95%CI:1.051~11.388),breastfeed(OR=2.451,95%CI:1.013~5.928)and EV71 infection(OR=7.964,95%CI:2.504~25.330)were the risk factors of death of HFMD. Conclusions It is necessary to improve the capacity of clinical diagnosis,together with improvement molecular diagnosis for identifying the virus type of HFMD in order to diagnose the HFMD cases earlier.More attention should be paid to these HFMD severe cases with age less than 1 year old and EV71 infection as well as strengthened rural area knowledge propaganda and education.