The level of interleukin-6 (IL-6) is correlated with prognosis and liver metastasis in colon cancer. However, the relationship between macrophage-derived and tumor-derived IL-6 in colon cancer remains unclear. We harvested the macrophage supernatant and studied the IL-6-inducing ability of the macrophage supernatant on the colon cancer cell line HT-29. The macrophage supernatant effectively induced IL-6 secretion of colon cancer cells in vitro. The macrophage supernatant and recombinant IL-6 neutralized with anti-IL-6 or ant-gp130 antibodies dramatically decreased the IL-6-induction ability of cancer cells. IL-6-induction occurred through phosphorylation of STAT3. We analyzed the surgical specimens of 126 patients with colon cancer using an immunohistochemical staining method and demonstrated the colocalization of macrophages and the expression of IL-6 in colon cancer patients. These results indicate that macrophages in tumor infiltrates could release IL-6, which in turn conditions colon cancer cells, causing them to secrete IL-6 themselves via phosphorylation of STAT3.