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Hypoxia-inducible factor 1a (HIF-1a) is a nuclear protein that is upregulated in many tumors and triggers biologic events intimately associated with aggressive tumor behavior. The aim of this study was to analyze the expression of HIF-1a, vascular endothelial growth factor (VEGF), Ki-67 and p53 in type I and type II endometrial adenocarcinoma. In total, 149 patients diagnosed with endometrial adenocarcinoma in our institute from 1995 to 2001 were included in this study, of which 108 were type I and 41 were type II endometrial adenocarcinoma. Patient demographics, clinical and pathological data were reviewed. Tissue microarrays were prepared from the paraffin blocks and immunohistochemistry was performed for antibodies against HIF-1a, VEGF, Ki-67 and p53. High expression of HIF-1a, VEGF, Ki-67 and p53 were significantly more frequent in type II than type I endometrial adenocarcinoma (Po0.001). HIF-1a expression was highly correlated with VEGF expression in the tumor cells (P ¼ 0.001). In type I endometrial adenocarcinoma, high expression of HIF-1a showed a significant correlation with higher grade of the tumor, depth of myometrial invasion, adnexal invasion and clinical stage. A similar correlation was not observed in type II endometrial adenocarcinoma. Surgical stage was the only independent prognostic marker for survival. In conclusion, high expression of HIF-1a is more frequent in type II than in type I endometrial adenocarcinoma. In type I endometrial adenocarcinoma, HIF-1a expression correlates with morphologic features of aggressiveness. In type II endometrial adenocarcinoma, there is no correlation between HIF-1a expression and these features. Thus, HIF-1a may play an important role in endometrial adenocarcinoma progression, particularly in type I endometrial adenocarcinoma. Additional investigations of HIF-1a as a biomarker of aggressive potential and as a novel target for therapeutics in endometrial adenocarcinoma are warranted. Hypoxia-inducible factor 1 (HIF-1) is a nuclear protein that activates gene transcription specifically in response to reduced cellular oxygen concentration and therefore acts as a marker for hypoxia. It is a dimeric protein with two subunits, a and b. HIF-1a is the specific hypoxia-regulated subunit. 2 Hypoxia results in stabilization of HIF-1a, facilitating nuclear HIF-1a binding and restoration of oxygen homeostasis by inducing glycolysis and angiogenesis through upregulation of vascular endothelial growth