PURPOSE: Lactate dehydrogenase (LDH-5) is a major lactate dehydrogenase isoenzyme catalyzing the transformation of pyruvate to lactate for anaerobic acquisition energy. In this study, the expression of LDH-5 was assessed in the normal and malignant endometrium. Its role in prognosis and tumor angiogenesis and hypoxia was also examined. EXPERIMENTAL DESIGN: Tissue specimens from 68 patients with clinical stage I endometrial adenocarcinoma of the endometrioid cell type and 20 samples from normally cycling endometrium were investigated immunohistochemically for the expression of LDH-5. The vascular density and the expression of angiogenesis/hypoxia-related proteins (VEGF, HIF1alpha, HIF2alpha, phosphorylated VEGFR2/KDR, VEGF/KDR complex) were also assessed. RESULTS: Unlike other normal epithelia, the glandular endometrial cells consistently expressed LDH-5 suggesting a role of this enzyme in the normal menstrual cycle. Endometrial adenocarcinomas displayed LDH-5 expression in 31/68 (45.5%) cases with those having a high LDH-5 expression being connected with a low lymphocytic response; this may suggest an important role of LDH-5 and, presumably, lactate release in tumor escape from host immuno-surveillance. More importantly, LDH-5 was significantly associated with the expression of phosphorylated VEGFR2/KDR receptors in cancer cells and tumor-associated vasculature. LDH-5 was one of the most powerful and independent prognostic variables. CONCLUSIONS: LDH-5 expression is an independent prognostic marker in endometrial cancer, linked with impaired host immune response and activation of VEGFR2/KDR receptors in both cancer cells and tumor-associated vasculature. Adjuvant radio-chemotherapy may, therefore, be useful in these cases, while the administration of VEGF- tyrosine kinase receptor inhibitors emerges as a therapeutic option.