The aim of this study was to identify novel and reliable serum markers related to the prognosis of colorectal cancer (CRC) patients and to assess the association between selected markers and clinical outcome. We performed experiments using cytokine arrays to investigate the cytokine profiles in serum from stage IV CRC patients, compared with those of stage I patients. Serum CXCL10 was measured using an ELISA in 218 CRC patients and 17 normal volunteers to clarify the association of CXCL10 with clinical outcome. The mean serum CXCL10 concentration in CRC patients was significantly higher compared to that in normal volunteers. Serum CXCL10 levels increased significantly in accordance with the progression of UICC stage classification. Serum CXCL10 was significantly associated with high pathological T stage, the presence of vascular invasion and distant metastasis. Elevated serum CXCL10 levels were significantly associated with poor survival in all stages or in stage I-III with curative patients, respectively, and were an independent marker in predicting liver metastasis. Immunohistochemical analysis showed that CXCL10 was expressed in cancer cells at primary tumor and liver metastases sites, and in normal liver tissue surrounding metastatic cancer cells. Comprehensive analysis using cytokine arrays identified the novel serum prognosis marker CXCL10. Preoperative high serum levels of CXCL10 were associated with poor prognosis and liver metastasis in CRC.