Abstract: Objective To study the clinical and epidemiological features of severe hand-foot-mouth disease (HFMD) cases from maternal and child health care hospital of Guangxi Zhuang Autonomous Region from 2012 to 2016, distribution of etiology and their changes in order to control and prevent the disease. Methods The clinical data were collected from HFMD cases in department of pediatrics in our institution from 2012 to 2016. Epidemiological characteristics of severe HFMD, including years, ages, genders and regions were retrospectively analyzed. EV71, CoxA16 and enterovirus were detected via RT-PCT. Results A total of 52 861 cases were reported during 2012 to 2016, among which 870 (1.65%) cases were severe cases. The results showed that two seasonal peaks appeared between April to July and August to October. The proportion of 1 to 2-year-old children was the largest, accounting for 45.40% of all cases, and it was 21.15% in children aged 2 to 3 years old. Children aged under 5 constituted 97.59% of all cases. There was a male predominance of severe HFMD cases, with a male-to-female ratio of 2.25:1. The majority (88.15%) of cases occurred in those children who stayed at home. The percentage of children in kindergartens was 10.47%. The proportion of cases from Xixiangtang and Jiangnan region was 21.98% and 16.46% respectively. Among the 870 samples, 704 (80.92%) were tested positive for EV, including EV71(40.34%), Cox A16(6.39%) and other EV (53.27%)type. Out of 14 fatal cases, EV71 was identified in 85.71% of all death cases. Other EV was identified in 7.14% of all death cases. The prevalent strain was EV71 in 2012 and in 2014, and it was other EV in other years. Conclusion There was a seasonal fluctuation about the epidemic severe HFMD. Severe HFMD was more likely to occur in children under five years old. High-risk populations were scattered children and children in childcare, and boys were more easily affected than girls. EV was the major pathogen causing severe HFMD, and EV71 was the predominant pathogen leading cause of severe and death cases. EV71 showed popular superiority strains every one or two years.