Lysosome-associated protein transmembrane-4β (LAPTM4B) is a novel cancer-related gene that is upregulated in many tumors, and which plays important roles in carcinogenesis. It has two alleles, LAPTM4B 1 and LAPTM4B 2. LAPTM4B 1 contains only one copy of a 19-bp sequence in the first exon, whereas LAPTM4B 2 contains two tight tandem segments. Previous studies have shown that LAPTM4B 2 is a risk factor for susceptibility and prognosis of many tumors. The present study investigated the relationship between LAPTM4B polymorphism and non-small cell lung cancer (NSCLC) susceptibility and prognosis. We identified LAPTM4B genotypes with polymerase chain reaction (PCR) in peripheral blood samples. In the adjusted multivariate logistic regression analysis, we found that LAPTM4B 1/2, LAPTM4B 2/2 exhibited 1.48-fold [95% confidence interval (CI), 1.076-2.037] and 2.855-fold (95%CI, 1.722-4.734) increases in the risk of developing NSCLC compared with non-LAPTM4B 2 carriers. Furthermore, our results showed that overall survival time and disease-free survival time of patients with LAPTM4B 2 were significantly shorter than in patients carrying LAPTM4B 1 (P=0.001 and P=0.001, respectively). In addition, multivariate Cox regression analysis revealed that LAPTM4B 2 was also an independent prognostic factor for NSCLC. These results suggest that LAPTM4B polymorphisms may be a prospective marker for evaluating the risk and prognosis of NSCLC.