Aims & Objectives: carry out a multicenter epidemiological study of the severe hand foot and mouth disease (HFMD), to find out the clinical features, laboratory results, risk factors of severe HFMD. Methods A collaborative study group was established.Prospective epidemiologic approaches were adopted. Results We collected 128 HFMD cases in stage 2, 61 HFMD cases in stage 3, 37 HFMD cases in stage 4 from April 2014 to October 2016. The age ranged from 2 months to 13 years old, the mean age was 2.4 ± 1.3 years old, younger than 3 years accounted for 86.3%. Fever was obsevered in all the severe HFMD, mean temperature was 39.2 ± 0.7 (37.5~42) –, fever lasted for 4.54 ± 2.89 (1–16) days. 78.3% had typical rashes, 14.6% had atypic rashes, 7.1% had no rashes. The mean heart rate was 162.7 ± 28.6 (68–243) /min. The mean respiratory rate was 39.0 ± 8.4 (25–68) /min. Respiratory rhythm abnormality in stage 2, 3, 4 was 9.4%, 16.4%, 56.8% respectively. The mean blood glucose in stage 2, 3, 4 was 8.73 ± 3.18, 9.17 ± 3.99, 12.4 ± 4.74 respectively. The incidence of coma in stage 2, 3, 4 was 5.6%, 15.3%, and 47.2% respectively. Tachycardia, hypertension, drowsiness, dystonia, coma, respiratory rate increase, respiratoy rhythm abnormality, CRT more than 3 seconds, hyperglycemia, fever lasted more than 3 days were risk factors for severe HFMD. Conclusions The severe patients had obvious changes in the nervous, respiratory and circulatory system. Tachycardia, hypertension, drowsiness, dystonia, coma, respiratory rate increase, respiratoy rhythm abnormality, CRT more than 3 seconds, hyperglycemia, fever lasted more than 3 days were risk factors for severe HFMD.