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Abstract: Polymorphisms in 3′ untranslated region (UTR) of cancer-related genes might affect their regulation by microRNAs (miRNAs) and thereby contribute to carcinogenesis. In this study, we screened single nucleotide polymorphisms (SNPs) in 3′ UTR of cancer-related genes and investigated their effects on risk of lung cancer. First, we genotyped seven SNPs in a Chinese Han population with 600 lung cancer patients and 600 matched healthy controls and found that compared with the TT genotype of rs2239680 in 3′ UTR of baculoviral IAP repeat containing 5 (BIRC5), C allele was associated with a significantly increased risk of lung cancer and advanced pathologic stage, with the odds ratio for participants carrying the CT or CC genotype being 1.50 [95% confidence interval (CI) 1.20–1.89, P <0.01] and 2.29 (95% CI 1.64–3.18, P <0.01), respectively. These results were further replicated and confirmed in another independent population with 1000 lung cancer cases and 1000 matched healthy controls. In support of the postulation that the 3′ UTR SNP may directly affect miRNA-binding site, reporter gene assays indicated BIRC5 was a direct target of miR-335, and the rs2239680 T>C change resulted in altered regulation of BIRC5 expression. Moreover, BIRC5 was over expressed in lung cancer tissues compared with the normal lung tissues, and the protein levels of BIRC5 correlated with SNP genotypes in normal lung tissues. Our findings defined a 3′ UTR SNP in human BIRC5 oncogene that may increase individual susceptibility to lung cancer probably by attenuating the interaction between miR-335 and BIRC5. [Copyright &y& Elsevier]