Abstract: Objective To investigate the risk factors of severe cases of hand-foot-mouth disease (HFMD) in southern Hainan, and to provide evidence for prevention and control. Methods Case control study was used with 663 cases of children with severe hand-footmouth disease in southern region of Hainan province from January 2012 to December 2015 as a case group, and 624 cases with mild disease in the same period as the control group. The baseline data of case group and control group were recorded by questionnaires, and the risk factors of severe cases of hand-foot-mouth disease were analyzed by univariate and multivariate non conditional logistic regression analysis. Results Univariate analysis showed that children age< 3 years old, scattered children, living in rural areas, family population ≥ 6, number of children in the family ≥ 3, per capita living space ≤ 15 m², missed diagnosis at frst clinic visit, time interval between onset and initial visit ≤ 1 day, vaccination one month before the onset, contact with sick children, poor hand hygiene in children, poor hand hygiene in nursing staff, clinic visit ≥ 2 times in 6 months, increased peripheral blood white blood cell count, and EV71 virus infection were associated with severe cases of hand-foot-mouth disease(P< 0.05). Multivariate logistic regression analysis showed that scattered children, number of children in the family, missed diagnosis at frst clinic visit, contact with sick children, poor hand hygiene in children, clinic visit ≥ 2 times in 6 months, EV71 virus infection were independent risk factors for severe cases with hand-foot-mouth disease. The OR and 95%CI were 1.653(1.564-1.875), 2.085(1.957-2.316), 5.842(5.623-8.274), 1.816(1.735-2.024), 3.387(3.266-6.741), 2.247(2.105-2.618), 2.518(2.341-2.826), respectively. Conclusion Major risk factors of hand-foot-mouth disease are shown in these severe cases, and the corresponding measures should be taken to strengthen the monitoring of the disease, and prevent the occurrence of severe cases of hand-foot-mouth disease.