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Existing studies reported higher altitudes reduce the COVID-19 infection rate in the United States, Colombia, and Peru. However, the underlying reasons for this phenomenon remain unclear. In this study, regression analysis and mediating effect model were used in a combination to explore the altitudes relation with the pattern of transmission under their correlation factors. The preliminary linear regression analysis indicated a negative correlation between altitudes and COVID-19 infection in China. In contrast to environmental factors from low-altitude regions (<1500 m), high-altitude regions (>1500 m) exhibited lower PM2.5, average temperature (AT), and mobility, accompanied by high SO 2 and absolute humidity (AH). Non-linear regression analysis further revealed that COVID-19 confirmed cases had a positive correlation with mobility, AH, and AT, whereas negatively correlated with SO 2 , CO, and DTR. Subsequent mediating effect model with altitude-correlated factors, such as mobility, AT, AH, DTR and SO 2 , suffice to discriminate the COVID-19 infection rate between low- and high-altitude regions. The mentioned evidence advance our understanding of the altitude-mediated COVID-19 transmission mechanism. [Display omitted] • High altitudes reduce the COVID-19 infection. • Altitude changes the levels of MSI, DTR, AH, AT, and SO 2. • Multiple mediating model confirmed altitude-dependent COVID-19 infection. [ABSTRACT FROM AUTHOR]