Introduction: Published data on the association between XPD Lys751Gln and Asp312Asn gene polymorphism and lung cancer risk are inconclusive. Methods: To derive a more precise estimation of the relationship, a meta-analysis was performed. Results: A total of 22 studies including 15,507 subjects for XPD Lys751Gln genotype and 13,198 subjects for XPD Asp312Asn genotype were examined. For XPD Lys751Gln genotype, significantly increased lung cancer risk was associated with two variant genotypes (CC versus AA: odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.12-1.42, p = 0.473 for heterogeneity; C allele carriers versus AA: OR = 1.18, 95% CI = 1.08-1.36, p = 0.732 for heterogeneity). When stratified by ethnicity, significantly increased risks were found among Caucasians but not in Asians. For XPD Asp312Asn genotype, significantly increased lung cancer risk was associated with two variant genotypes (AA versus GG: OR = 1.24, 95% CI = 1.09-1.42, p = 0.104 for heterogeneity; the A allele carriers versus GG: OR = 1.35, 95% CI = 1.13-1.57, p = 0.219 for heterogeneity). When stratified analysis by ethnicity, significantly increased risks were found among Asians but not in Caucasians. In the subgroup analyses by smoking status, there were no significant associations among the nonsmoker subgroup; however, significantly increased lung cancer risks were found in the smoking group. CONCLUSION: This meta-analysis suggests that the XPD Lys751Gln and Asp312Asn gene polymorphisms are associated with lung cancer risk, the C allele of XPD Lys751Gln genotype is an increased risk factor for developing lung cancer among Caucasians and in smokers, and the A allele of XPD 312 genotype is also an increased risk factor among Asians and in smokers. © 2010 by the International Association for the Study of Lung Cancer.