ABSTRACT: Background:The novel human coronavirus disease 2019 (COVID-19) pandemic has claimed more than 240,000 lives worldwide, causing tremendous public health, social, and economic damages. While the risk factors of COVID-19 are still under investigation, environmental factors, such as urban air pollution, may play an important role in increasing population susceptibility to COVID-19 pathogenesis. Methods:We conducted a cross-sectional nationwide study using zero-inflated negative binomial models to estimate the association between long-term (2010-2016) county-level exposures to NO2, PM2.5 and O3 and county-level COVID-19 case-fatality and mortality rates in the US. We used both single and multipollutant models and controlled for spatial trends and a comprehensive set of potential confounders, including state-level test positive rate, county-level healthcare capacity, phase-of-epidemic, population mobility, sociodemographic, socioeconomic status, behavior risk factors, and meteorological factors. Results:1,027,799 COVID-19 cases and 58,489 deaths were reported in 3,122 US counties from January 22, 2020 to April 29, 2020, with an overall observed case-fatality rate of 5.8%. Spatial variations were observed for both COVID-19 death outcomes and long-term ambient air pollutant levels. County-level average NO2 concentrations were positively associated with both COVID-19 case-fatality rate and mortality rate in single-, bi-, and tri-pollutant models (p-values<0.05). Per inter-quartile range (IQR) increase in NO2 (4.6 ppb), COVID-19 case-fatality rate and mortality rate were associated with an increase of 7.1% (95% CI 1.2% to 13.4%) and 11.2% (95% CI 3.4% to 19.5%), respectively. We did not observe significant associations between long-term exposures to PM2.5 or O3 and COVID-19 death outcomes (p-values>0.05), although per IQR increase in PM2.5 (3.4 ug/m3) was marginally associated with 10.8% (95% CI: -1.1% to 24.1%) increase in COVID-19 mortality rate. Discussions and Conclusions:Long-term exposure to NO2, which largely arises from urban combustion sources such as traffic, may enhance susceptibility to severe COVID-19 outcomes, independent of long-term PM2.5 and O3 exposure. The results support targeted public health actions to protect residents from COVID-19 in heavily polluted regions with historically high NO2 levels. Moreover, continuation of current efforts to lower traffic emissions and ambient air pollution levels may be an important component of reducing population-level risk of COVID-19 deaths.