〔Abstract〕 Objective Hypoxia-inducible factor 2 A(HIF2 A) and vascular endothelial growth factor A(VEGFA) are important genes in the hypoxia-inducible pathway, the association of rs13419896 in HIF2 A and rs833061 in VEGFA with lung cancer recently becomes the focus. Our study is to demonstrate genetic association rs13419896 and rs833061 with lung cancer in Chinese population. Methods A case-control study was performed between 438 patients with lung cancer and 456 healthy controls. The collected samples were genotyped by Taqman Genotyping method, and the association and clinical characteristics were analyzed. Results The rs13419896 A allele decreased the risk of lung cancer [OR=0.72, 95%CI(0.58～0.88),P=0.001 1], comparing to rs13419896 G allele, and further analysis found that rs13419896-AA significantly decreased risk of lung cancer in the additive model[OR=0.74, 95%CI(0.61～0.90),P=0.002]. After adjustment the effects of smoke, alcohol and age, rs13419896 genotypes still significantly decreased the risk of lung cancer[OR=0.75, 95%CI(0.60～0.93),P=0.009]. However, the rs13419896 genotypes had no significant relationship with pathological types and clinical stages in lung cancer, and there was no association between lung cancer and rs833061 in VEGFA. Conclusion The results show that polymorphism of rs13419896 in HIF2 A is associated with lung cancer in Hainan area of China. It can be used as a potential genetic marker for lung cancer after validation by multi-center and large sample studies.