Vinyl chloride monomer (VCM) is a human carcinogen. However, the exact mechanism of carcinogenesis remains unclear. 2-Chloroethylene oxide (CEO) and 2-chloroacetaldehyde (CAA), the metabolic intermediates of VCM, induce DNA damage which is mainly repaired by the nucleotide excision repair (NER) pathway. The XPD gene product and the related XPB protein are DNA helicases that are involved in transcription and NER. Polymorphisms of XPD have been implicated in chemical exposure-related health effects. In order to explore the mechanism of VCM-related health effects, a special matched case-control design (exposed workers with DNA damage and without damage) was used to investigate the association between the gene polymorphisms of XPD and DNA damage in 106 male and 44 female workers occupationally exposed to VCM. Exposure and anthropometrics information was collected through in-person interview. Such information was then used to calculate cumulative exposure doses of the workers. DNA damage in peripheral lymphocytes was measured by the single cell gel electrophoresis (SCGE) assay that identified DNA strand breaks. Genomic DNA from lymphocytes was used in genotyping assays. Genotypes of XPD Ile199Met, XPD Asp312Asn, and XPD Lys751Gln were identified by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) procedure. The results indicate that the genotypes of XPD 751Lys/Gln and Gln/Gln were significantly associated with the expression of DNA damages (OR 2.21, P<0.05, 95% CI 1.01-5.13). An interesting observation is the reduction of DNA damage for workers with high VCM exposure and possessing the XPD Asp/Asn and Asn/Asn genotypes (OR 0.33, 95% CI 0.11-0.95). Polymorphisms of XPD may therefore be a major reason of genetic susceptibility in VCM-induced DNA damage and health consequences.