Colorectal cancer is the second most common cause of cancer-related death. Novel prognostic factors should be identified and validated to refine the present tumor-node-metastasis system. The presence of immune cells infiltrating colorectal cancers is a common phenomenon. However, the current belief is that clinically detectable human tumors escaping immune surveillance are no longer kept in check by the immune cells of the tumor microenvironment. Despite studies showing the influence of immune cell infiltrates on the behavior of colorectal carcinomas, this parameter is not currently recognized as a reliable prognostic factor. We showed that the nature, functional orientation, density, and location of immune cells within distinct tumor regions could provide a prognostic factor superior to and independent of criteria related to the anatomic extent of the tumor. The strength of the immune reaction identified in our studies could advance our understanding of cancer evolution and have important consequences for clinical practice.