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Studying the influence of weather conditions on the COVID-19 epidemic is an emerging field. However, existing studies in this area tend to utilize time-series data, which have certain limitations and fail to consider individual, social, and economic factors. Therefore, this study aimed to fill this gap. In this paper, we explored the influence of weather conditions on the COVID-19 epidemic using COVID-19-related prefecture-daily panel data collected in mainland China between January 1, 2020, and February 19, 2020. A two-way fixed effect model was applied taking into account factors including public health measures, effective distance to Wuhan, population density, economic development level, health, and medical conditions. We also used a piecewise linear regression to determine the relationship in detail. We found that there is a conditional negative relationship between weather conditions and the epidemic. Each 1 °C rise in mean temperature led to a 0.49% increase in the confirmed cases growth rate when mean temperature was above −7 °C. Similarly, when the relative humidity was greater than 46%, it was negatively correlated with the epidemic, where a 1% increase in relative humidity decreased the rate of confirmed cases by 0.19%. Furthermore, prefecture-level administrative regions, such as Chifeng (included as "warning cities") have more days of "dangerous weather", which is favorable for outbreaks. In addition, we found that the impact of mean temperature is greatest in the east, the influence of relative humidity is most pronounced in the central region, and the significance of weather conditions is more important in the coastal region. Finally, we found that rising diurnal temperatures decreased the negative impact of weather conditions on the spread of COVID-19. We also observed that strict public health measures and high social concern can mitigate the adverse effects of cold and dry weather on the spread of the epidemic. To the best of our knowledge, this is the first study which applies the two-way fixed effect model to investigate the influence of weather conditions on the COVID-19 epidemic, takes into account socio-economic factors and draws new conclusions. • The relationship between weather conditions and COVID-19 epidemic was studied using two-way fixed effect model. • Individual, social and economic factors such as public health measures were also taken into account. • Mean temperature (when > -7 °C) and relative humidity (when >46%) showed significantly negative associations with confirmed cases growth rate. • "Warning cities" were defined based on "dangerous weather". • Strict public health measures and public opinion can mitigate the weather effect. [ABSTRACT FROM AUTHOR]