Aim: The aim of this study was to examine the clinicopathological influence of tumor-infiltrating cluster of differentiation (CD) 163(+) macrophages and CD8(+) T-cells, and to clarify the prognostic effects of these cells in patients with invasive extrahepatic bile duct cancer (EHBC). Materials and Methods: The numbers of CD8(+) T-cells in cancer cell nests and CD163(+) macrophages in tumor stroma were evaluated using immunohistochemistry in 101 resected EHBC specimens. Correlations with clinicopathological variables and overall survival were analyzed. Results: Perihilar EHBC and perineural invasion were significantly associated with a low number of tumor-infiltrating CD8(+) T-cells. Poorly-differentiated histology and nodal metastasis were significantly associated with a high number of tumor-infiltrating CD163(+) macrophages. A combination of high number of CD8(+) T-cells and low number of CD163(+) macrophages was independently related to better overall survival in the whole patient cohort (hazard ratio=0.127, p<0.001) and in patients treated with adjuvant chemotherapy (hazard ratio=0.139, p=0.021). Conclusion: Infiltrating CD163(+) macrophages in tumor stroma and CD8(+) T-cells in cancer cell nests have a prognostic impact in patients with EHBC following resection and also after adjuvant chemotherapy.