OBJECTIVES: Hand, foot, and mouth disease (HFMD) is a viral infectious disease that poses a substantial threat in the Asia-Pacific region. It is widely reported that meteorological factors are associated with HFMD. However, the relationships between air pollutants and HFMD are still controversial. In addition, the interactive effects between meteorological factors and air pollutants on HFMD remain unknown. To fill this research gap, we conducted a time-series study. DESIGN: A time-series study. SETTING AND PARTICIPANTS: Daily cases of HFMD as well as meteorological and air pollution data were collected in Chengdu from 2011 to 2017. A total of 184 610 HFMD cases under the age of 15 were included in our study. OUTCOME MEASURES: Distributed lag nonlinear models were used to investigate the relationships between HFMD and environmental factors, including mean temperature, relative humidity, SO(2), NO(2), and PM(10). Then, the relative excess risk due to interaction (RERI) and the proportion attributable to interaction were calculated to quantitatively evaluate the interactions between meteorological factors and air pollutants on HFMD. Bivariate response surface models were used to visually display the interactive effects. RESULTS: The cumulative exposure-response curves of SO(2) and NO(2) were inverted 'V'-shaped and 'M'-shaped, respectively, and the risk of HFMD gradually decreased with increasing PM(10) concentrations. We found that there were synergistic interactions between mean temperature and SO(2), relative humidity and SO(2), as well as relative humidity and PM(10) on HFMD, with individual RERIs of 0.334 (95% CI 0.119 to 0.548), 0.428 (95% CI 0.214 to 0.642) and 0.501 (95% CI 0.262 to 0.741), respectively, indicating that the effects of SO(2) and PM(10) on HFMD were stronger under high temperature (>17.3°C) or high humidity (>80.0%) conditions. CONCLUSIONS: There were interactive effects between meteorological factors and air pollutants on HFMD. Our findings could provide guidance for targeted and timely preventive and control measures for HFMD.