Both air pollution and genetic factors independently influence the development of COPD. However, few studies focus on gene and air pollution synergic interaction in COPD.We assessed the independent and synergic effects between susceptibility genes, PM2.5 and other air pollutants and COPD.We assessed the independent and synergic effects between susceptibility genes, Particulate Matter 2.5(PM2.5) and other air pollutants and COPD. We collected 21,255 participants from Taiwan Biobank with health, lifestyle, and gene data. Air pollution exposure was estimated aerosol optical(AOD-PM2.5) prediction method for PM2.5 concentration prediction and inverse distance weighting (IDW) method to evaluate other pollutants (O3, NO2, CO, SO2). Genome-wide single nucleotide polymorphism(SNP) genotyping related to COPD with pint<1 × 10−6 and gene—environment interaction was test by “adaptive combination of Bayes factors method” (ADABF) method.In our study, the participants exposure to PM2.5 concentration more than 22.45µg/m3 was significantly associated with COPD (OR=1.599 (95% CI=1.181- 2.165)) after multivariate adjustments. There were 87 SNPs reach significant level. Eleven SNPs of 87 revealed the relationship between NO2 and COPD interaction. SCMH1 (Scm Polycomb Group Protein Homolog 1) on chromosome 1, WDPCP (WD Repeat Containing Planar Cell Polarity Effector) on on chromosome 1, TESC-AS1 (TESC antisense RNA 1) on Chromosome 12, five SNPs on chromosome 5, two SNPs on Chromosome 9 and one SNPs on chromosome 20 showed the gene-environment interaction in COPD cases.Our study identified a positive association between PM2.5 exposure and COPD risk, with eleven SNPs showing interactions with NO₂. Prior Asian studies reported TP63 rs4488809 interacting with non-small cell lung cancer (NSCLC) and positive association of PM2.5 and COPD. Variations in pollutant composition and exposure levels may influence results. As a cross-sectional study, causal relationships between PM2.5, genetic susceptibility, and COPD could not be definitively established.Long-term PM2.5 exposure was associated with increased COPD risk, and synergistic effects between genetic factors and NO₂ were observed. Further prospective cohort studies are warranted to validate these findings