Objective To study the death risk factors in children with severe hand, foot and mouth disease (HFMD). Methods A total of 164 children with severe HFMD between May 2010 and September 2012 were recruited and classified into death and survival groups according to their prognosis. The differences in general information, clinical signs and symptoms and laboratory examinations were compared between the two groups. The multivariate logistic regression analysis was used to identify death risk factors in children with severe HFMD. Results There were significant differences in the incidences of atypical rash, persistent fever, dyspnea, pulmonary hemorrhage, heart rate increase, blood pressure abnormalities, cold sweat, capillary refill time>3 seconds and frequent seizures, and blood glucose, serum creatine kinase and serum lactate levels between the death and the survival groups (P<0.05). The multivariate logistic regression analysis showed three independent death risk factors for children with severe HFMD: pulmonary hemorrhage (OR=9.466, 95%CI: 1.786-21.256), abnormal blood pressure (OR=5.224, 95%CI: 1.012-28.985) and elevated serum lactate level (OR=2.154, 95%CI: 1.020-8.253). Conclusions Pulmonary hemorrhage, abnormal blood pressure and elevated serum lactate are major death risk factors for children with severe HFMD.