Recent studies have shown that 5p15.33 is one of the chromosomal regions that is most consistently altered in lung cancer; common variants that are located in this region have been genotyped in various populations. However, the genetic contribution of these variants to carcinogenesis is relatively unknown. A clinic-based case-control study in Shanghai was undertaken on 196 patients with lung cancer and 229 healthy individuals. TERT rs2736100 and CLPTM1L rs401681 and rs402710 were genotyped using the ABI TaqMan Allelic Discrimination assay. For rs2736100, the G variant and the GG genotype were more frequent, whereas the TT genotype was less frequent in patients with lung adenocarcinoma than in controls. The CT genotype at rs401681 was more common and the TT genotype was rare in patients, and the differences were significant between lung adenocarcinoma patients and controls. This was also true for rs402710. Moreover, the frequency of the GGCTCT haplotype was higher and the TTTTTT frequency was lower in patients, especially those with lung adenocarcinoma. Aberrant linkage disequilibrium among the three SNPs was found in patients with lung adenocarcinoma. We conclude that multiple variants at 5p15.33 contribute to susceptibility to lung adenocarcinoma.