Hand-foot-mouth disease (HFMD) is a frequently occurring epidemic and has been an important cause of childhood mortality in China. Given the disease's significant impact nationwide, the epidemiological characteristics and spatio-temporal clusters in Fuyang from 2008 to 2013 were analysed in this study. The disease exhibits strong seasonality with a rising incidence. Of the reported HFMD cases, 63·7% were male and 95·2% were preschool children living at home. The onset of HFMD is age-dependent and exhibits a 12-month periodicity, with 12-, 24- and 36-month-old children being the most frequently affected groups. Across the first 60 months of life, children born in April [relative risk (RR) 8·18], May (RR 9·79) and June (RR 8·21) exhibited an elevated infection risk of HFMD relative to January-born children; the relative risk compared with the reference (January-born) group was highest for children aged 24 months born in May (RR 34·85). Of laboratory-confirmed cases, enterovirus 71 (EV71), coxsackie A16 (Cox A16) and other enteroviruses accounted for 60·1%, 7·1% and 32·8%, respectively. Spatio-temporal analysis identified one most likely cluster and several secondary clusters each year. The centre of the most likely cluster was found in different regions in Fuyang. Implications of our findings for current and future public health interventions are discussed.