Objective To investigate the relationship between M2 macrophages and prognosis of patients with human colorectal cancer by using CD163 protein as a marker. Methods The clinical data and paraffin samples of 648 patients with newly diagnosed colorectal cancer and the paraffin specimens of the tumor tissues after operation were collected from Jan. 2010 to Dec. 2011 in the Department of Colorectal Surgery, Changhai Hospital, Navy Medical University (Second Military Medical University). All patients were diagnosed by postoperative pathology. Paracancerous tissues of the above 38 patients, normal colorectal mucosal tissues of 37 patients undergoing hemorrhoidectomy (PPH), and colorectal adenoma tissues of 33 patients receiving endoscopic treatment served as controls. All specimens were made into tissue microarrays, and the expression of CD163 protein was detected by immunohistochemistry. The relationships between the expression of CD163 protein and clinicopathological parameters and prognosis of patients with colorectal cancer were analyzed. Results The expression level of CD163 was related to the degree of tumor differentiation, serum carbohydrate antigen 19-9 (CA19-9) and tumor recurrence and metastasis (all P<0.05). Survival analysis showed that the high CD163 expression group had lower disease-free survival and overall survival rates and poor prognosis compared with the low CD163 expression group (P<0.001). Cox multivariate analysis showed that serum expression levels of carcinoembryonic antigen (CEA) and CD163 were independent prognosis factors of patients with colorectal cancer (P<0.05). Conclusion M2 macrophage marker CD163 has a good reference value for the prognosis of patients with colorectal cancer.