Erythropoietin via erythropoietin receptor effectively prevents anemia, giving reasons for a clinical use of erythropoietin in patients with colorectal cancers. However, erythropoietin seems to promote survival of the neoplastic cells in hypoxic environment. The aim of this study was to evaluate immunohistochemically the expression of erythropoietin and erythropoietin receptor in 136 primary colorectal cancers with a correlation to different anatomo-clinical features. Erythropoietin correlated with erythropoietin receptor in colorectal cancers (r = 0.547, P < .00001). Erythropoietin and erythropoietin receptor expressions were statistically higher in adenocarcinomas versus mucinous carcinomas (P = .05 and P = .03, respectively) and in moderately (G2) versus poorly differentiated (G3) tumors (P = .001 and P = .02, respectively). This in vivo study is the first study that provides evidences for the presence of erythropoietin and erythropoietin receptor in human colorectal cancer. The expressions of these proteins strictly depended on grading because the better histological differentiation probably comes from trophic influence of erythropoietin and erythropoietin receptor.