Background: HFMD is an infectious disease caused by enterovirus. The disease is benign and self-limiting within 7-10 days. However, in some cases, the disease progresses to severe neurological, cardiovascular complications and can be fatal if not detected and treated in time. Identifying some risk factors of severe HFMD is very important. Based on these risk factors, doctors at grassroots health system can quickly classify HFMD patients and adopt appropriate handling approaches: either transfer HFMD patients at high risk complications to the hospital early to closely monitor for subsequent treatment, while those with low risk can be given outpatient care after counseling patients’ parents. Methodology: a case-control study based on hospital was conducted on 150 cases of severe HFMD patients (from level 2b or higher) and 150 cases of mild HFMD patients (level 1, 2a), matching by age, gender, ethnicity and area of residence. Both cases and controls were hospitalized at the same hospital and were positive for EV or EV71 (PCR). Cases and controls were compared in terms of factors which can affect the severity of HFMD. Results: Logistic regression showed that the risk factors before patients’ hospitalization include: malnutrition, not exclusive breastfeeding in the first 6 months, low maternal education, and poor care for sick children. The risk factors after patients’ hospitalization include: peak temperature ≥ 39oC, with no signs of mouth ulcers, startling history, increase of leukocytosis, and EV71 as pathogen. Conclusion: Factors increasing the risk of severe HFMD include stunting malnutrition (OR = 1.84 - 95% CI: 1.05 to 3.22); not be exclusively breastfed for the first 6 months (OR = 2.03 - 95% CI: 1.08 to 3.84); Low maternal education (OR = 2.77 - 95% CI: 1.06 to 7.28); poor maternal care for patients (OR = 3.93 - 95% CI: 2.40 to 6.44); peak temperature ≥ 39oC (OR = 3.63 95% CI-: 1.91 to 6.90); No signs of oral ulcers (OR = 2.45 95% CI-: 1.28 to 4.69); Startling history (OR = 9.93 95% CI-: 4.89 to 20.14); increase of leukocytosis ≥ 11.0 (K/µl) (OR = 2.52 95% CI-: 1.36 to 4.69); EV71-infected patients (OR = 2.46 95% CI-: 1.29 to 4.69). Key words: risk factors, severer hand-foot-mouth disease