DNA repair plays a critical role in protecting the genome from insults of cancer-causing agents, such as those found in tobacco smoke. Therefore, reduced DNA repair capacity can increase the susceptibility to smoking-related cancers. Recently, several polymorphisms have been identified in the xeroderma pigmentosum group G (XPG) gene, and it is possible that these polymorphisms may affect the DNA repair capacity, thereby modulating cancer susceptibility. We investigated the relationship between the His1104Asp polymorphism in the XPG gene and the risk of lung cancer. The study population consisted of 310 lung cancer patients and 311 healthy controls who were frequency (1:1) matched based on age and sex. The Asp/Asp genotype was more frequent in the controls (28.9%) than in the cases (18.7%) and associated with a significantly decreased risk of lung cancer [adjusted odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37-0.80] when the combined His/His and His/Asp genotype was used as the reference. The protective effect of the Asp/Asp genotype against lung cancer was statistically significant in the older subjects (adjusted OR = 0.51, 95% CI = 0.37-0.80), males (adjusted OR = 0.54, 95% CI = 0.35-0.83), and lighter smokers (adjusted OR = 0.48, 95% CI = 0.25-0.94) in a stratification analysis. When the lung cancers were analyzed by histologic type, the Asp/Asp genotype was associated with a significantly decreased risk of squamous cell carcinoma (adjusted OR = 0.55, 95% CI = 0.34-0.88) and small cell lung cancer (adjusted OR = 0.44, 95% CI = 0.20-0.97), but non-significant decreased risk of adenocarcinoma (adjusted OR = 0.64, 95% CI = 0.36-1.12). These results suggest that the XPG codon 1104 polymorphism contributes to genetic susceptibility to lung cancer.