Hand, foot, and mouth disease (HFMD) has spread widely and led to high disease burden in many countries. In this study, we aimed to analyze the interaction of the main pathogens of HFMD using a mathematical model.A dataset on reported HFMD cases was collected from April, 2009 to December, 2017 in Changsha City. A long-term etiological surveillance was conducted focusing on the pathogens of the disease including enterovirus A71 (EV71), coxsachievirus A16 (CA16), and other enteroviruses. A susceptible-infectious-recovered model was adopted to calculate the reproduction number during the ascending period of reported cases (defined as Rasc) and the descending period (defined as Rdes).About 214,178 HFMD cases (including clinically diagnosed cases and confirmed cases) were reported in Changsha City, among which 31 were death cases with a fatality of 0.01%. The number of reported HFMD cases increased yearly with a Linear model of "f(t) = 18542.68 + 1628.91t" where f(t) and t referred to number of reported cases and sequence of year, respectively. The fatality of the disease decreased yearly with a linear model of "f(t) = - 0.012 + 0.083/t". About 5319 stool or anal swab specimens were collected from the reported cases. Among them, 1201 were tested EV71 positive, 836 were CA16 positive, and 1680 were other enteroviruses positive. Rasc and Rdes of HFMD was 1.34 (95% confidence interval [CI]: 1.28-1.40) and 0.73 (95% CI: 0.69-0.76), respectively. EV71 and CA16 interacted with each other, and the interaction between EV71 and other enteroviruses and the interaction between CA16 and other enteroviruses were both directional. However, during the reported cases decreasing period, interactions only occurred between EV71 and other enteroviruses and between CA16 and other enteroviruses. These interactions all decreased Rasc but increased Rdes of affected pathogens.The interactions of the pathogens exist in Changsha City. The effective reproduction number of the affected pathogen is adjusted and verges to 1 by the interaction.