Nogo protein, encoded by gene reticulon-4 (RTN4), includes three major isoforms by different splicing, named Nogo-A Nogo-B and Nogo-C. Nogo proteins play an important role in the apoptosis of cells, especially in tumor cells. RTN4 single nucleotide polymorphisms (SNPs) can influence the efficiency of transcription and translation thus being related with an individual's predisposition to cancer. The CAA insertion/deletion polymorphism (rs34917480) within RTN4 3'-UTR has been reported to be associated with many cancer types. In order to investigate the relationship between this polymorphism and susceptibility to non-small cell lung cancer (NSCLC) in the Chinese population, we conducted the present case-control study including 411 NSCLC patients and 471 unrelated healthy controls. The genotype distributions were significantly different between cases and controls (p=0.014). We found that the del allele could significantly increase NSCLC risk (ins/ins vs ins/del: p=0.007, OR 1.46, 95%CI=1.11-1.93; dominant model: p=0.004, OR 1.47, 95%CI=1.13-1.92 and allele model: p=0.008, OR 1.35, 95%CI=1.08-1.67). This association was stronger in participants over 60 years old, males and smokers. We therefore conclude that the CAA insertion/deletion polymorphism (rs34917480) contributes to non-small cell lung cancer risk in Chinese population. Age, sex and environmental exposure are also related to carcinogenic effects of rs34917480.