BACKGROUND: Numerous studies have demonstrated the potential association between rainfall and hand, foot and mouth disease (HFMD), but the results are inconsistent. This study aimed to quantify the relationship between rainfall and HFMD based on a multicity study and explore the potential sources of spatial heterogeneity. METHODS: We retrieved the daily counts of childhood HFMD and the meteorological variables of the 143 cities in mainland China between 2009 and 2014. A common time series regression model was applied to quantify the association between rainfall and HFMD for each of the 143 cities. Then, we adopted the meta-regression model to pool the city-specific estimates and explore the sources of heterogeneity by incorporating city-specific characteristics. RESULTS: The overall pooled estimation suggested a nonlinear exposure-response relationship between rainfall and HFMD. Once rainfall exceeded 15?mm, the HFMD risk stopped increasing linearly and began to plateau with the excessive risk ratio (ERR) peaking at 21?mm of rainfall (ERR?=?3.46, 95% CI: 2.05, 4.88). We also found significant heterogeneity in the rainfall-HFMD relationships (I(2) =?52.75%, P