Genome-wide association studies have provided evidence that common variation at 5p15.33 [telomerase reverse transcriptase ( TERT )-cleft lip and palate transmembrane 1-like ( CLPTM1L )], 6p21.33 and 15q25.1 ( CHRNA5-CHRNA3 ) influences lung cancer risk and cancer types with strong environmental risk factors. To independently validate these associations, we compared 5p15.33 (rs402710, rs401681), 6p21.33 (rs4324798) and 15q25.1 (rs1051730, rs16969968 and rs8034191) genotypes in 365 non-small cell lung cancer cases and 440 controls. Consistent with published data, variant genotypes of 5p15 (rs402710), 6p21 and 15q25 showed dose-dependent associations with lung cancer risk. To examine if variants influence the impact of environmental risk factors on lung carcinogenesis, we studied the relationship between genotype and levels of bulky aromatic/hydrophobic DNA adducts in lung tissue adjacent to tumor from 204 lung cancer cases. The risk allele of rs402710 ( TERT-CLPTM1L locus) was associated with significantly higher levels of bulky aromatic/hydrophobic DNA adducts ( P = 0.02). These data demonstrate a potential association between the TERT-CLPTM1L variant and levels of bulky DNA adducts measured by 32 P-postlabeling and hence a basis for susceptibility to the development of lung cancer.