Children of severe hand, foot, and mouth disease (HFMD) often present with same clinical features as those of mild HFMD during the early stage, yet later deteriorate rapidly with a fulminant disease course. Our goal was to: (1) develop a machine learning system to automatically identify cases with high risk of severe HFMD at the time of admission; (2) compare the effectiveness of the new system with the existing risk scoring system. Data on 2,532 HFMD children admitted between March 2012 and July 2015, were collected retrospectively from a medical center in China. By applying a holdout strategy and a 10-fold cross validation method, we developed four models with the random forest algorithm using different variable sets. The prediction system HFMD-RF based on the model of 16 variables from both the structured and unstructured data, achieved 0.824 sensitivity, 0.931 specificity, 0.916 accuracy, and 0.916 area under the curve in the independent test set. Most remarkably, HFMD-RF offers significant gains with respect to the commonly used pediatric critical illness score in clinical practice. As all the selected risk factors can be easily obtained, HFMD-RF might prove to be useful for reductions in mortality and complications of severe HFMD.