Abstract Background Little research has been conducted on the spatio-temporal relationship between the severe cases and the enteroviruses infections of hand, foot and mouth disease (HFMD). This study aimed to investigate epidemic features and spatial clusters of HFMD incidence rates and assess the relationship between Enterovirus 71 (EV71) and Coxsackievirus A16 (CoxA16) and severe cases of HMFD in Gansu province, China. Methods Weekly county-specific data on HFMD between 1st January and 31st December 2018 were collected from the China Infectious Disease Information System (CIDIS), including enterovirus type (EV71 and CoxA16), severe and non-severe cases in Gansu province, China. Temporal risk [frequency index (α), duration index (β) and intensity index (γ)] and spatial cluster analysis were used to assess epidemic features and identify high-risk areas for HFMD. Time-series cross-correlation function and regression model were used to explore the relationship between the ratios of two types of viruses (i.e. EV71/Cox16) (EC) and severe cases index (i.e. severe cases/non-severe cases) (SI) of HFMD. Results Some counties in Dingxi City, Gansu were identified as a hot spot for the temporal risk indices. Time-series cross-correlation analysis showed that SI was significantly associated with EC (r = 0.417, P
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