Objective:To explore the effect factors of serve Hand-foot-mouth disease(HFMD)among children. Methods: A hospital-based case-control study was conducted on two groups of children matched by sex,age and hospital of time. Interview was carried out with uniform designed questionnaires between the case-group with serious complication and control-group with mild symptoms. Cox’s proportional hazards regression analysis was then performed. The pathogen of HFMD was confirmed by RT-PCR. Results: Time intervals between onset date and admission date(OR=1.668,95%CI:1.307-2.128),heating(OR=5.181,95%CI:1.939-13.844)-fever duration(OR=1.562,95%CI:1.142-2.135),stiff neck(OR=3.188,95%CI:1.055-9.634),the higher number of white blood cell(OR=1.038,95%CI:1.013-1.064)and neutrophilic granulocyte(OR=1.235,95%CI:1.108-1.378),and Enterovirus71 infection(OR=5.069,95%CI:2.472-10.393)were risk factors of HFMD among children with serious symptoms,However,lymph-cell counts increase(OR=0.968,95%CI:0.944-0.992),Children infected with CoxA16(OR=0.191,95%CI:0.094-0.388)were the protection factors. The risk factors were found with multivariate analysis,and were associated with time intervals between onset date and admission date(OR=1.668,95%CI:1.122-2.477),the higher number of white blood cell(OR=1.304,95%CI:1.080-1.575)and neutrophilic granulocyte(OR=1.088,95%CI:1.001-1.184),The protections factors was associated with CoxA16 infection(OR=0.169,95%CI:0.038-0.753).Conclusion: To strengthen clinical surveillance and etiology surveillance of HFMD disease,early diagnosis and early treatment can effectively prevent children developing severe hand-foot-and-mouth disease possibility.