Background: To find out useful tools to evaluate the prognosis of colon cancer, this study investigated how c-FLIPL and tumor-infiltrating lymphocytes (TILs) are correlated with the prognosis of patients with stage IIIB colon cancer. Methods: 180 cases of pathologically proven specimens with stage IIIB colon cancer (T3N1M0, AJCC, 7th edition) were collected at Sun Yat-sen University Cancer Center. The expression of c-FLIPL and the density of TILs in tumor tissues were examined through immunohistochemical analysis. The correlation of c-FLIPL and TILs, with the prognosis of patients was analyzed. Results: C-FLIPL was correlated with an unfavorable overall survival (OS). The densities of CD8+ and CD45RO+ T cells were associated with a favorable OS, whereas Foxp3+ Treg cells were related to an unfavorable OS. However, the relationship between TILs and prognosis varied for two groups of patients that were divided according to c-FLIPL expression. In the group with high c-FLIPL expression, a high density of CD8+ and CD45RO+ T cells or a low density of Foxp3+ Treg cells was correlated with a short OS; In the group with low c-FLIPL expression, a high density of CD8+ and CD45RO+ T cells or a low density of Foxp3+ Treg cells was correlated with a long OS. Conclusion: This study revealed that the relationship between the density of TILs and the prognosis of colon cancer depended on the expression of c-FLIPL, indicating that the clinical outcome of immune response depended on not only the subtypes of TILs but also the genetic background of cancer cells.