Lactate dehydrogenase 5 (LDH5) is one of the five LDH isoenzymes and, apparently, the most important for promoting anaerobic glycolysis. LDH5 is transcriptionally regulated by the hypoxia inducible factors (HIF) 1α and 2α. In this study, the possible aggressive advantages that colorectal tumours may gain from a high LDH5 content was investigated. To this end, 75 colorectal adenocarcinomas were studied immunohistochemically for the expression of LDH5, and the results were related to tumor differentiation, lymph node and distant metastases, the expression of HIF1α and HIF2α, vascular density (VD) and vascular endothelial growth factor (VEGF). A high LDH5 content was noted in 51 of 75 (68%) colorectal adenocarcinomas. The reactivity was nuclear and/or cytoplasmic. Nuclear LDH5 reactivity was correlated with lymph node involvement and distant metastases. There was a direct association between LDH5 up-regulation and HIF1α and HIF2α accumulation. HIF1α was linked with VEGF, VD and also with extramural invasion, nodal and distant metastases. It is concluded that a high LDH5 content in tumor cells is directly related to an up-regulated HIF pathway and is lnked with an aggressive phenotype in colorectal adenocarcinomas.