Abstract: Objective To explore risk factors for severe hand-foot-mouth disease (HFMD) in Hainan and provide scientific basis for severe HFMD prevention and control. Methods Counties were stratified into three layers according to the proportion of severe HFMD. Two counties were selected in each layer. A total of 125 severe HFMD cases and 125 mild cases were investigated in 6 counties. A 1:1 matched case-control study was conducted to explore risk factors for severe HFMD. Results Univariate analysis showed that following factors were distributed differently between two groups:village/private clinic as first diagnosis hospital, not breastfed, infected with enteroviruses 71 (EV71), a peak body temperature>39℃, period from onset to diagnosis ≥ 2 days. Conclusions Strengthening etiology surveillance, releasing the early warning according the variation of EV71 proportion, advocating breastfeeding, prohibiting village/private clinic receiving fever children under 5 years old and strengthening training to improve the diagnosis level might contribute to decrease risk for severe HFMD.