Abstract: Objective To explore the risk factors for non-enterovirus A71 (EV-A71)-associated severe hand, foot and mouth disease (HFMD) for early identification and treatment of the disease.Methods HFMD patients from the People's Hospital of Baoan in Shenzhen City were enrolled from May, 2015 to November, 2016. Clinico-epidemiological data were recorded and patient samples were collected. The enterovirus serotype was identified using real-time PCR. Then the non-EV-A71 patients were divided into two groups, with 185 cases and 185 controls, respectively. Influential factors of severe cases were screened through multi-factor conditional likelihood ratio method.Results Fever temperature above 39℃ (OR=6.61,95% CI:3.17-13.81), papule (OR=2.82,95% CI:1.40-5.69), rash on feet (OR=2.05, 95% CI:1.08-3.90), delay in seeing the doctor for one day (OR=3.44,95% CI:1.56-7.58), complications at birth (OR=7.37,95% CI:1.66-32.70), non-breast feeding (OR=1.89, 95% CI:1.01-3.54), playing a lot in the neighborhood (OR=2.92,95% CI:1.44-5.92), frequent toys chewing (OR=2.27,95% CI:1.13-4.53) were the risk factors of severe cases (all P<0.05).Conclusions Identifying risk factors of non-EV-A71-associated severe HFMD by clinical and laboratory methods will promote early diagnosis and treatment of the disease and provide evidence for health education.