BACKGROUND: There is limited evidence about the association between ambient temperature and the incidence of pediatric hand, foot, and mouth disease (HFMD) nationwide in China. OBJECTIVES: We examined the childhood temperature-HFMD associations across mainland China, and we projected the change in HFMD cases due to projected temperature change by the 2090s. METHODS: Data on daily HFMD (children 0-14 y old) counts and weather were collected from 362 sites during 2009-2014. Daily temperature by the 2090s was downscaled under the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Temperature-HFMD associations were quantified using a two-stage Poisson regression with a distributed lag nonlinear model. The impact of changes in temperature on the incidence of HFMD was estimated by combining the fitted temperature-HFMD associations with projected temperatures under each scenario, assuming a constant population structure. Sensitivity analyses were performed to assess the influence of primary model assumptions. RESULTS: During 2009-2014, >11 million HFMD cases were reported. In most regions, the temperature-HFMD association had an inverted U shape with a peak at approximately 20°C, but the association leveled off or continued to increase in the Inner Mongolia and Northeast regions. When estimates were pooled across all regions and the population size was held constant, the projected incidence of HFMD increased by 3.2% [95% empirical confidence interval (eCI): −13.5%, 20.0%] and 5.3% (95% eCI: −33.3%, 44.0%) by the 2090s under the RCP 4.5 and 8.5 scenarios, respectively. However, regional projections suggest that HFMD may decrease with climate change in temperate areas of central and eastern China. CONCLUSION: Our estimates suggest that the association between temperature and HFMD varies across China and that the future impact of climate change on HFMD incidence will vary as well. Other factors, including changes in the size of the population at risk (children 0-14 y old) will also influence future HFMD trends.