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The transmission and prevalence of Hand, Foot and Mouth Disease (HFMD) are affected by a variety of natural and socio-economic environmental factors. This study aims to quantitatively investigate the non-stationary and spatially varying associations between various environmental factors and HFMD risk. We collected HFMD surveillance cases and a series of relevant environmental data from 2013 to 2021 in Xi'an, Northwest China. By controlling the spatial and temporal mixture effects of HFMD, we constructed a Bayesian spatiotemporal mapping model and characterized the impacts of different driving factors into global linear, non-stationary and spatially varying effects. The results showed that the impact of meteorological conditions on HFMD risk varies in both type and magnitude above certain thresholds (temperature: 30 °C, precipitation: 70 mm, solar radiation: 13000 kJ/m2, pressure: 945 hPa, humidity: 69%). Air pollutants (PM2.5, PM10, NO2) showed an inverted U-shaped relationship with the risk of HFMD, while other air pollutants (O3, SO2) showed nonlinear fluctuations. Moreover, the driving effect of increasing temperature on HFMD was significant in the 3-year period, while the inhibitory effect of increasing precipitation appeared evident in the 5-year period. In addition, the proportion of urban/suburban/rural area had a strong influence on HFMD, indicating that the incidence of HFMD firstly increased and then decreased during the rapid urbanization process. The influence of population density on HFMD was not only limited by spatial location, but also varied between high and low intervals. Higher road density inhibited the risk of HFMD, but higher night light index promoted the occurrence of HFMD. Our findings further demonstrated that both ecological and socioeconomic environmental factors can pose multiple driving effects on increasing the spatiotemporal risk of HFMD, which is of great significance for effectively responding to the changes in HFMD epidemic outbreaks. [ABSTRACT FROM AUTHOR]