Objective To investigate the relationship between single nucleotide polymorphisms of xeroderma pigmentosum complementary group D (XPD) and cytidine deaminase (CDA) gene and susceptibility to lung cancer, and explore the influence of the interaction between smoking and gene polymorphisms on the risk of development of lung cancer. Methods Case-control study was performed on 103 patients with lung cancer and 103 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was employed to determine  the  genotype distribution of XPD exon 10 G→A (Asp312Asn) and 23A→C (Lys751Gln) and that of CDA exon 79A→ C (Lys27Gln) and 208G→ A (Ala70 Thr). Results There was no significant difference in genotype distribution of XPD312 and XPD751 between two groups (P＞0.05). However, smoking in combination with mutation at locus 751 of XPD increased the risk of development of lung cancer (P=0.044), and the risk of development of lung cancer increased 6.13 times with mutations at both loci 312 and 751 of XPD (P=0.047). There was no significant difference in genotype distribution of CDA Lys27Gln and CDA Ala70 Thr between two groups (P>0.05). There was no significant difference in genotype distribution of XPD and CDA among different pathological types. Conclusion Smoking in combination with mutation at locus 751 of XPD may increase the risk of development of lung cancer, and mutation at both loci 312 and locus 751 of XPD may increase the risk of development of lung cancer.