This study investigates the association between long-term air pollution exposure and the risk of Parkinson's disease (PD), considering genetic susceptibility. Using data from 312,009 individuals without a prior PD diagnosis, the researchers estimated annual mean concentrations of PM2.5, PM10, NO2, and NOx, and calculated a polygenic risk score (PRS) to assess individual genetic risk for PD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between air pollutants, genetic risk, and incident PD. Over a median follow-up of 12.07 years, 2356 PD cases were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs of 1.247 (1.089–1.427) and 1.201 (1.052–1.373), respectively. Each 10 µg/m³ increase in NO2 and PM10 exposure was associated with elevated HRs of 1.089 (1.026–1.155) and 1.363 (1.043–1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145–3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912–3.048). The findings suggest that exposure to air contaminants increases PD risk, particularly in individuals genetically predisposed to high susceptibility. The study highlights the importance of genetic factors in modifying the relationship between air pollution and PD risk. The results indicate that reducing air pollution levels could provide potential benefits for individuals genetically predisposed to PD. The study also identifies the need for further research to understand the mechanisms underlying the association between air pollution and PD, as well as to explore the impact of additional air pollutants and refine genetic risk assessments.This study investigates the association between long-term air pollution exposure and the risk of Parkinson's disease (PD), considering genetic susceptibility. Using data from 312,009 individuals without a prior PD diagnosis, the researchers estimated annual mean concentrations of PM2.5, PM10, NO2, and NOx, and calculated a polygenic risk score (PRS) to assess individual genetic risk for PD. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between air pollutants, genetic risk, and incident PD. Over a median follow-up of 12.07 years, 2356 PD cases were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs of 1.247 (1.089–1.427) and 1.201 (1.052–1.373), respectively. Each 10 µg/m³ increase in NO2 and PM10 exposure was associated with elevated HRs of 1.089 (1.026–1.155) and 1.363 (1.043–1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145–3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912–3.048). The findings suggest that exposure to air contaminants increases PD risk, particularly in individuals genetically predisposed to high susceptibility. The study highlights the importance of genetic factors in modifying the relationship between air pollution and PD risk. The results indicate that reducing air pollution levels could provide potential benefits for individuals genetically predisposed to PD. The study also identifies the need for further research to understand the mechanisms underlying the association between air pollution and PD, as well as to explore the impact of additional air pollutants and refine genetic risk assessments.