Objective To investigate the difference of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in endometrial cancer and para-carcinoma tissues, and to explore the clinical significance of hypoxia and the two proteins in the development and progression of endometrial cancer. Methods From Jan. 2011 to Dec. 2012, 128 patients with endometrial cancer underwent surgery in Tongji Hospital of Tongji University. The expression of HIF-1α and VEGF in cancer tissues and paired para-carcinoma tissues was detected using immunohistochemical method. The patients were followed up regularly, and the relationship between the expression of HIF-1α and VEGF and the prognosis of the patients was analyzed. The hypoxic cell model of human endometrial cancer was constructed to detect the expression of HIF-1α and VEGF proteins and observe the cell proliferation, invasion and apoptosis. Results The positive rates of HIF-1α and VEGF in cancer tissues were significantly higher than those in the para-carcinoma tissues (both P<0.05). The positive rate of HIF-1α was higher in the patients with lymph node metastasis, high histological grade, maximal tumor dimeter ≥ 4 cm or positive progesterone receptor (all P<0.05). The positive rate of VEGF was higher in the patients with lymph node metastasis, high histological grade, deep myometrial invasion, maximal tumor dimeter ≥ 4 cm, positive estrogen receptor, positive progesterone receptor or high pathological stage (all P<0.05). The 5-year overall survival rate of the patients with negative HIF-1α was significantly higher than that of the patients with positive HIF-1α (P<0.05), while there was no significant difference in the 5-year overall survival rate between the patients with negative and positive VEGF (P>0.05). In the hypoxic cell model of human endometrial cancer, the expression levels of HIF-1α and VEGF were significantly increased, cell proliferation and invasion were significantly increased, and the cell apoptosis was significantly reduced (all P<0.05). Conclusion HIF-1α and VEGF are related to the progress of endometrial cancer, and positive expression of HIF-1α indicates a poor prognosis.