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Hand, foot, and mouth disease (HFMD) is a major public health concern in the Asia–Pacific region. Previous studies have implied that ambient air pollution may affect the incidence of HFMD, but the results among different regions are inconsistent. We aimed to deepen the understanding of the associations between air pollutants and HFMD by conducting a multicity study. Daily data on childhood HFMD counts and meteorological and ambient air pollution (PM2.5, PM10, NO2, CO, O3, and SO2) concentrations in 21 cities in Sichuan Province from 2015 to 2017 were collected. A spatiotemporal Bayesian hierarchical model framework was established, and then a distributed lag nonlinear models (DLNMs) was constructed to reveal exposure-lag-response relationships between air pollutants and HFMD while controlling for spatiotemporal effects. Furthermore, given the differences in the levels and seasonal trends of air pollutants between the basin region and plateau region, we explored whether these associations varied between different areas (basin and plateau). The associations between air pollutants and HFMD were nonlinear, with different lag responses. Low NO2 concentrations and both low and high PM2.5 and PM10 concentrations were associated with a decreased risk of HFMD. No significant associations between CO, O3, and SO2 and HFMD were found. The associations between air pollutant concentrations and HFMD were different between the basin and plateau regions. Our study revealed associations between PM2.5, PM10, and NO2 concentrations and HFMD, deepening the understanding of the relationships between air pollutants and HFMD. These findings provide evidence to support the formulation of relevant prevention measures and the establishment of an early warning system. [ABSTRACT FROM AUTHOR]