Rationale: The association between fine particulate matter (particulate matter ⩽2.5 μm in aerodynamic diameter, PM_2.5) and lung cancer incidence in nonsmokers (LCINS) remains inconsistent. Objectives: To investigate the association between long-term PM_2.5 exposure and LCINS in a Chinese population and to assess the modifying effect of genetic factors. Methods: Time-dependent Cox proportional hazard models were used to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) of PM_2.5 with LCINS risk and LCINS-related mortality. The polygenic risk score was constructed to further explore the interactions between genetic risk and PM_2.5 exposure. In addition, the population attributable fraction of PM_2.5 to lung cancer risk and mortality was calculated. Measurements and Main Results: The results demonstrated significant associations between PM_2.5 exposure and LCINS incidence (HR, 1.10 per 10 μg/m³; 95% CI, 1.04-1.17 per 10 μg/m³) and mortality (HR, 1.17 per 10 μg/m³; 95% CI, 1.08-1.27 per 10 μg/m³). Compared with the lowest-risk group, individuals exposed to the high PM_2.5 concentration (⩾50.9 μg/m³) and high genetic risk (top 30%) exhibited the highest LCINS incidence (HR, 2.01; 95% CI, 1.39-2.87) and mortality (HR, 2.30; 95% CI, 1.38-3.82). A significant additive interaction between PM_2.5 and genetic risk on LCINS incidence was observed. Approximately 33.6% of LCINS cases and 48.5% of LCINS-related deaths in China could be prevented if PM_2.5 concentrations were reduced to meet World Health Organization guidelines. Conclusions: Long-term exposure to outdoor PM_2.5 increases LCINS risk and LCINS-related mortality, especially in populations with high genetic risk. Strengthening air pollution control measures in China has the potential to significantly reduce the burden of LCINS.

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