The implication of genetic factors in predisposition to cancer is a recognized fact. The Cleft lip and palate transmembrane 1-like (CLPTM1L) gene resides in a locus in the chromosome 5p15.33 region that is associated with lung cancer susceptibility and has a role in carcinogenesis. We conducted a case-control study in a Chinese population of 309 pathologically confirmed lung cancer patients and 310 controls to investigate the effect of variant genotypes within the CLPTM1L locus on susceptibility to lung cancer and sensitivity to cisplatin-based chemotherapy. We genotyped nine single nucleotide polymorphisms (SNPs) within the CLPTM1L locus and examined their correlation with lung cancer risk and treatment response using χ (2) and unconditional logistic regression analysis. We identified rs451360 as a novel SNP associated with lung cancer risk in the Chinese Han population. The "T" allele of rs451360 was associated with decreased risk of lung cancer (p = 0.007, odd ratio (OR) = 0.59, 95 % confidence interval (CI): 0.40-0.87). Significant multiplicative interactions were observed between gender and polymorphisms of rs402710, the "T/T" genotype of which was associated with decreased lung cancer risk in male patients (p = 0.016, OR = 0.35, 95 % CI: 0.17-0.73). CLPTM1L polymorphisms did not affect the tumor sensitivity to cisplatin combination chemotherapy in our study patients. The results of the present study suggest a potential association between CLPTM1L variants and lung cancer risk in the Chinese Han populations.