Hand, foot, and mouth disease (HFMD) is a common pediatric disease, whose outcome depends of the enterovirus genotype infecting the patient. The present study is focused on the potential diagnostic value and the role of circulating microRNA-494 (miR-494) in enterovirus 71-induced more severe form of HFMD. We included 102 children with enterovirus 71 (EV71)-induced HFMD, 42 coxsackievirus A16 (CA16)-induced HFMD and 102 healthy controls. The plasma and serum samples were collected. The expression level of circulating miR-494 was determined by RT-PCR method. Moreover, ROC curve has been drawn to evaluate the sensitivity and specificity of circulating miR-494 for the diagnosis of EV71-induced HFMD. Furthermore, the correlation between the circulating miR-494 and the levels of interleukin 6 (IL-6), interleukin 4 (IL-4) and interferon γ (IFN-γ) in the serum of patients were analyzed. Circulating miR-494 was significantly increased in plasma of children with EV71-induced HFMD compared with the healthy children or CA16-induced HFMD, and level of miR-494 in the EV71 severe group was significantly higher than the EV71 mild group. Moreover, results of ROC analysis suggested that miR-494 is a sensitive biomarker to distinguish EV71 patients from healthy controls and CA16 patients. Furthermore, IL-6 and IFN-γ were elevated in serum of patients with EV71-induced HFMD and the level of circulating miR-494 in patients with EV71-induced HFMD was positively correlated with the serum levels of both IL-6 and IFN-γ, respectively. Circulating miR-494 was abnormally up-regulated in plasma of the children with EV71-induced HFMD, and miR-494 may serve as potential biomarker for the diagnosis and treatment of the disease. Keywords: miR-494; HFMD; biomarker; enterovirus 71; inflammation.