CTLA-4 is a potent immunoregulatory molecule and plays a pivotal role in the negative regulation of T-cell proliferation and activation. Previously, the association between CTLA-4 +49A>G polymorphism and the risk of NSCLC has been investigated in several studies, however, their results were inconsistent. Therefore, we aimed to investigated the association between CTLA-4 +49A>G polymorphism and the risk of NSCLC in a Chinese population.We recruited 231 NSCLC patients and 250 healthy controls in the present case-control study. PCR-RFLP was used to analyze the polymorphism of CTLA-4. The chi-squared test was used to examine differences between NSCLC patients and controls. The odds ratio (OR) and its 95% confidence interval (95% CI) were obtained by logistic regression methodology to determine correlations between the CTLA-4 polymorphism and the incidence of NSCLC.When the AA genotype was used as the reference group, the GG genotype was significantly associated with increased risk for NSCLC (OR=2.181, 95% CI: 1.244-5.198; P=0.007), however, the AG genotype was not significantly associated with increased risk for NSCLC (OR=2.018, 95% CI: 0.826-3.881; P=0.099). Under the dominant model of inheritance, the AG+GG genotype was significantly associated with increased risk for NSCLC (OR=3.271, 95% CI: 1.827-4.559; P=0.015). In addition, the G allele had a 2.754-fold higher risk of NSCLC in comparison with the A allele (OR=2.754, 95% CI: 1.365-6.891, P=0.005).Our data provided evidence that the CTLA-4 +49A>G polymorphism is associated with increased risk of NSLCL in Chinese population.