Abstract: Objective　To explore the risk factors of severe hand, foot, and mouth disease (HFMD) complicated with cardiopulmonary failure. Methods　The clinical data of 179 children with severe HFMD admitted from December 2011 to December 2016 were retrospectively analyzed. According to whether the children were complicated with cardiopulmonary failure, they were divided into cardiopulmonary failure group (33 cases) and non-cardiopulmonary failure group (146 cases). Univariate analysis and multivariate logistic regression analysis were used to analyze the risk factors for severe HFMD with cardiopulmonary failure. Results　Univariate analysis revealed that there were significant differences between two groups in sex composition, tremor, disturbance of consciousness, irregular respiratory rhythm, limb weakness, slow heart rate, high blood pressure, peripheral circulation disorders, peripheral blood leukocyte count, pharyngeal reflex, frequent vomiting, abnormal cerebrospinal fluid leukocyte count, increased brain natriuretic peptide (BNP) levels, EV-71 infection, increased levels of S100 beta protein, neuronspecific enolase and troponin. Multivariate logistic regression analysis showed that frequent vomiting, peripheral circulation disorder, enterovirus EV-71 infection, irregular respiratory rhythm, and elevated BNP levels were five independent risk factors of severe HFMD with cardiopulmonary failure. Conclusions　Frequent vomiting, circulatory disturbances, EV-71 infection, respiratory rhythm dysfunction, and elevated BNP levels are indicative of severe HFMD complicated with cardiopulmonary failure.