To determine the effect of the DNA repair gene XPD Arg156Arg polymorphism on the risk of lung cancer in a North-Eastern Chinese population, a hospital-based case-control study was designed consisting of 149 newly diagnosis subjects with lung cancer and 137 cancer-free control subjects matched on age (+/-3 years), gender and ethnicity. In the whole study group, XPD Arg156Arg was not associated with risk of lung cancer. In stratified analyses, the variant A-allele of XPD Arg156Arg was associated with increased risk of adenocarcinoma of lung (AA/AC versus CC; adjusted OR=1.65; 95% CI=1.09-2.50) (P=0.02). Furthermore, the presence of one or two variant A-alleles was associated with increased risk for lung cancer (OR=2.49; 95% CI=1.10-5.64) (P=0.03) and adenocarcinoma of lung (OR=5.60; 95% CI=1.52-20.56) (P=0.005) among never-smokers only. These results suggest a possible gene-environment interaction. This is the first study to report a significant association of XPD Arg156Arg with risk of lung cancer.