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Background For high-risk II stage and III stage colon cancer (CC), the side effects and prognostic benefit of adjuvant chemotherapy need to be balanced. It is well known that tumor-associated macrophages (TAMs) play a key role in tumor progression and exist as heterogenous subpopulations. However, the clinical significance of them remains unknown. Methods Two independent cohorts of 360 and 126 consecutive colon cancer patients were enrolled from two medical centers of Zhongshan Hospital. The association of CXCR6 + TAMs with clinicalpathological characteristcs, prognosis and response to different duration of adjuvant chemotherapy (ACT) after radical surgery was analyzed. Immunofluorescence and Immunohistochemistry were performed to detect the density of CXCR6 + TAMs and activated CD8 + T cells. The cytokines from peripheral blood were also recorded to explore the immune microenvironment. Results The infiltration of CXCR6 + TAMs was higher in tissues, and increased with tumor stage. High density of CXCR6 + TAMs predicted worse overall survival (OS) in all CC patients, and was an independent risk factor verified by univariate and multivariate Cox regression analyses. For high-risk II stage and III stage patients with high density of CXCR6 + TAMs, better disease-free survival (DFS) and OS were observed in 6-month treatment group, especially for those who were male, mucinous, tumor size ≤ 4 cm, without nerve invasion and pMMR. There was a negative relationship between the density of CXCR6 + TAMs and CD8 + T cells, as well as activated CD8 + T cells. Higher level of IL-6, lower level of IL-2R and TNF-α were expressed in high CXCR6 + TAMs patients, which indicated that CXCR6 + TAMs contribute to an immunosuppressive microenvironment. Conclusion s CXCR6 + TAMs predicted prognosis and response to different durations of ACT in CC patients. CXCR6 + TAMs were asscoiated an immunosuppressive microenvironment and suppressed the activation of CD8 + T cells.