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Background Hypoxia-inducible factor (HIF) may play an important role in the process of tumorigenesis as well as tumor progression. The aim of this study was to compare the expression between HIF-1α and HIF-2α in tumor angiogenesis and the overall impact on patient prognosis in human non-small cell lung cancer (NSCLC).Methods In the current work we compared the immunohistochemical expression of HIF-1α and HIF-2α in surgical specimens of 140 patients with NSCLC in a tissue microarray study. Relationships between HIF-α expression and clinicopathological or angiogenic factors, including prognosis, were analyzed.Results High HIF-1α and HIF-2α expression was noted in 49/140 (35.0%) and in 64/140 (45.7%) of the cases,respectively. There was no direct correlation between HIF-1α and HIF-2α expression. Patients with advanced stage tumors had frequent high expression of HIF-2α (P=0.007), and we also found a significant correlation between HIF-2αand T or N stage (P=0.030 and 0.043, respectively). HIF-1α showed a marginal association with T stage (P=0.084),which showed a higher expression in early stage tumors. A significant correlation (P=0.045) was noticed between HIF-1αand vascular endothelial growth factor (VEGF) expression while the expression levels of thymidine phosphorylase (TP),cyclooxygenase (COX)-2 and microvessel density (MVD) were significantly higher in high HIF-2α tumors (P=0.020, 0.004,and 0.046, respectively). In addition, univariate analysis of overall survival demonstrated that HIF-2α expression, but not HIF-1α, was related to poor outcome (P=0.001) and it retained significant in multivariate analysis (P=0.036).Conclusions Taken together, we conclude that HIF-1α and HIF-2α may differentially regulate the major angiogenic factors in different stages of the tumor process in NSCLC. HIF-2α may play a dominant role in tumor angiogenesis and appears to be of obvious value as a significant prognostic factor in NSCLC.