Polymorphisms 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.