AbstractPolymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking‐related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (–449G→C, –371G→A, –27G→C, Val499Arg, PAT–/+, IVS11‐5C→A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency‐matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined –27CG+CC genotype was associated with a significantly increased risk for overall lung cancer compared to the –27GG genotype (adjusted OR = 1.97, 95% CI 1.22–3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the –371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined –371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09–4.00, p = 0.03). The PAT–/+, IVS11‐5C→A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29–0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36–1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35–0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11‐5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37–0.85, p = 0.007 and Bonferroni‐corrected p = 0.049), whereas haplotype 5 (1122111) containing the –27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41–5.87, p = 0.004 and Bonferroni‐corrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer. © 2005 Wiley‐Liss, Inc.