Aim: An epidemic of hand, foot and mouth disease (HFMD) occurred in Singapore between September and November 2000. During the epidemic, there were four HFMD‐related deaths and after the epidemic, another three HFMD‐related deaths. This study sought to determine the risk factors predictive of death from HFMD disease. Methods: The risk factors for fatal HFMD were determined by comparing clinical and laboratory findings between fatal cases (n= 7) and non‐fatal controls (n= 131) admitted between September 2000 and April 2001. Enterovirus 71 positive fatal cases (n= 4) and non‐fatal controls (n= 63) were also compared. Results: In total, 138 HFMD cases with a mean age of 32 mo were studied. The majority of fatal cases died from interstitial pneumonitis, of whom three also had brainstem encephalitis. Of the 131 non‐fatal cases, 3 had concomitant infections (respiratory syncytial virus bronchiolitis, right‐sided pneumonia, Haemo‐philus influenzae type b meningitis), 2 had aseptic meningitis, and 1 each had transient drowsiness, intravenous immunoglobulin‐related complications and transverse myelitis. By multivariate logistic regression analysis, atypical physical findings (p= 0.0006), raised total white cell count (p= 0.0128), vomiting (p= 0.0116) and absence of mouth ulcers (p= 0.043) were predictive of a fatal course. Although previous epidemics have described neurogenic pulmonary oedema as the main cause of death, the fatal cases in this study died mainly from interstitial pneumonitis alone or with myocarditis or encephalitis. Conclusion: Although HFMD is generally a benign disease, risk factors such as vomiting, absence of mouth ulcers, atypical presentation and raised total white cell count should alert the physician of a fatal course of illness.