Despite its primary hematopoietic function, erythropoietin (Epo) is a pleiotropic cytokine that exerts various biological functions in many different non-hematopoietic cells and cancers, and its stimulatory effects are mediated through activation of its receptor (EpoR). Recent studies have shown that Epo and EpoR may be involved in carcinogenesis, angiogenesis, and invasion. We have investigated the expression of Epo and EpoR in a series of 65 resected squamous cell carcinomas (SCC) of the tongue using immunohistochemical staining. The proportion of Epo and EpoR changes in them was greater than those in normal squamous epithelium (P<0.05). Epo expression was associated with age, density of microvessels, and the stage of the tumour (P<0.05). EpoR expression was associated with microvascular density alone (P<0.05). After adjusting for other clinicopathological factors, Epo and EpoR expression remained independent adverse prognosticators for postoperative survival (P<0.05). Our findings support the hypothesis that the Epo and EpoR systems influence the prognosis of carcinogenesis, angiogenesis, and malignant progression of SCC of the tongue, and confirm that Epo and EpoR are independent prognostic markers.