ObjectiveTo explore the risk factors associated with severe hand-food-mouth disease (HFMD) in Chongqing, in order to carry out intervention work in the future, provide reference for reducing the incidence and fatality rate of severe HFMD cases. MethodsNinety severe HFMD cases treated between 2011 and 2014 in Chongqing were enrolled as case group while another 90 mild HFMD cases were randomly selected as control group in the same period. All subjects’ parents or babysitters were asked to fill in a questionnaire which included demography, ways of babysitting, behavior and the like. All HFMD cases were diagnosed by both clinical symptoms and nuclear acid testing. Data were processed by EpiData 3.1 and analyzed by SPSS 13.0. ResultsSingle-factor analysis showed that there were 14 risk factors of severe HFMD including virus type, registered residence type, current address type, cultural degree of their caregivers, season of the onset, existence of fever and rash, first hospital diagnosis type, and whether the first diagnosis was HFMD (P ＜ 0.05) . Multifactor analysis showed the risk factors included the current rural residence type [OR=27.29, 95%CI (3.71, 200.72) ], misdiagnosis as disease other than HFMD in the first visit to the hospital [OR=141.03, 95%CI (12.43, 1 599.70) ], and virus type of EV71 [OR=244.32, 95%CI (18.99, 3 143.74) ]. ConclusionsActive surveillance should be carried out on the risk factors of severe HFMD. At the same time, active and effective preventive measures, and timely treatment of patients with severe HFMD can help to reduce the incidence and case fatality rate.