Mutant p53 protein and anti-p53 antibody in circulating blood can be detectedamong individuals with mutations of the p53 tumor suppressor gene. Plasma mutant p53 protein and anti-p53 antibody have also been associated with vinyl chloride monomer (VCM) exposure, although the mechanism of VCM-related carcinogenesis remains unclear. Polymorphisms of metabolic and DNA repair genes have been implicated in chemical exposure-related carcinogenesis. The aim of this study is to explore the association between polymorphisms of metabolic and DNA repair genes with mutant p53 protein and anti-p53 antibody expression induced by VCM. Study subjects comprised 333 male workers occupationally exposed to VCM. Plasma mutant p53 protein and anti-p53 antibody detected with ELISA were grouped together as p53 overexpression. Genotypes of cytochrome P450 2E1 (CYP2E1), aldehyde dehydrogenase 2 (ALDH2), glutathione S-transferase T1 (GSTT1), and X-ray repair cross-complementing group 1 (XRCC1, exon 10) genes were identified by the PCR. High VCM exposure group had significantly higher p53 overexpression as compared with low exposure group [odds ratio (OR), 2.1; 95% confidence interval (CI), 1.1-3.8]. Individuals having experienced a high VCM exposure and displaying a XRCC1 Gln-Gln genotype had a highest risk of p53 overexpression among those having different combinations of VCM exposure and XRCC1 genotypes (OR, 6.5; 95% CI, 1.7-24.2). Interestingly, those subjects reflecting a CYP2E1 c2c2 genotype among the low VCM-exposure group demonstrated a greater risk of p53 overexpression (OR, 9.8; 95% CI, 1.2-81.6) as compared with those experiencing a low VCM exposure and CYP2E1 c1c1/c1c2 genotypes. Additional analysis revealed that individuals possessing more susceptible XRCC1 Gln-Gln, CYP2E1 c2c2, ALDH2 1-2/2-2, and non-null GSTT1 genotypes were more likely to reveal p53 overexpression. Our results suggest that susceptible XRCC1 and CYP2E1 genotypes may modulate the mutation of the p53 gene among VCM-exposed workers.