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It is unclear whether G protein-coupled receptor 61 (GPR61) affecting body weight, plays a role in the association between birth weight and weather. This study aimed to assess the effects of prenatal weather and GPR61 on birth weight. A total of 567 mother-newborn pairs were recruited in Houzhai Center Hospital during 2011–2012. We detected the maternal and neonatal GPR61 promoter methylation levels, and obtained meteorological and air pollution data. A positive association was observed between maternal and neonatal GPR61 methylation levels, and both of them were affected by precipitation, relative humidity (RH) and daily temperature range (DTR). Birth weight was associated negatively with RH and positively with DTR (P < 0.05). A significant association was observed between birth weight and neonatal GPR61 methylation. We observed that maternal GPR61 methylation seemed to modify associations between weather and birth weight (P interaction < 0.10), while neonatal GPR61 methylation mediated the effects of RH and DTR on birth weight (P < 0.05). Our findings revealed the significant associations among prenatal weather, GPR61 methylation and birth weight. Maternal GPR61 methylation may modify the susceptibility of birth weight to prenatal weather conditions, while neonatal GPR61 methylation may be a bridge of the effects of prenatal RH and DTR on birth weight. [ABSTRACT FROM AUTHOR]