BACKGROUND: This study aims to clarify the association between exposure levels, SNPs, and DNA methylation in residents living in areas with multiple industrial pollutants. METHODS: We compared DNA methylation between high (HE) and low exposure (LE) groups, and analyzed association between urine concentrations of As, Hg, and V with DNA methylation, respectively among 159 residents near No. 6 Naphtha Cracking Complex in Taiwan. HE (n=78) and LE (n=81) were based on urine PAHs exposure biomarker 1-OHP and V concentrations. All participants were analyzed for 11 pollutants urine exposure biomarkers, DNA methylation, and 11 SNPs. RESULTS: Urine levels of 1-OHP, V, As, Hg, Cr, Mn, Sr, and Tl were significantly increased in HE compared to LE. We identified 68 CpG probes corresponding to 45 known human genes using Wilcoxon’s rank sum test comparing between HE and LE. We used DAVID for pathway analysis and found 16 pathways associated with exposure in KEGG pathway hsa04940: Type I diabetes mellitus (two gene hits PTPRN2, HLA-B,). We further used correlation analysis and found 70 CpG probes associated with urinary As levels, two with Hg, and 46 with V, which correspond to 62, none, and 32 known human genes, respectively. GSEA pathway analysis found four biological pathways associated with As (including ascorbate and aldarate metabolism), four with Hg (including linoleic acid metabolism), while no pathways were found associated with V. Fisher’s exact test and Wilcoxon rank sum test results showed 11 SNPs significantly associated with CpG probes methylation. Linear regression revealed rs11085020 (NFIC) and rs199442 (NSF) could be associated with exposure, the translated proteins of which are associated with activating gene transcription and replication, and vesicle-mediated transport, respectively. CONCLUSIONS: We identified industrial pollutants-associated SNPs, DNA methylation, and biological pathways among exposed population. KEYWORDS petrochemical industry, air pollution, heavy metal, polycyclic aromatic hydrocarbon, DNA methylation, SNPs