We aimed to determine the prognostic values of 39 circulating cytokines in Chinese patients with metastatic colorectal cancer (CRC) and to develop a novel cytokine-based prognostic classifier (CBPC) for prognostic prediction. A total of 176 patients were divided into two cohorts based on the date of first-line chemotherapy. The first 99 cases were assigned to the training cohort, and the remaining 77 cases were assigned to the validation cohort. Thirty-nine cytokines were simultaneously analyzed in the patient serum samples using multiplex bead-based Luminex technology. We used support vector machine-based methods and Cox proportional hazards models to develop a CBPC from the training cohort, which we then validated using the second patient cohort. Univariate analysis showed that FGF-2, TGFa, Flt-3L, GM-CSF, INFa2, GRO, IL-10, MCP-3, MDC, sIL-2Ra, IL-2, IL-7, IL-8, MCP-1, MIP-1b, TNFa and VEGF were significant risk factors affecting the overall survival (OS) of both the training cohort and the validation cohort. We developed a CBPC to predict the OS of metastatic CRC patients using these 17 cytokines (sensitivity, 0.835; specificity, 0.800). In the validation cohort, the CBPC was found to have significant power in predicting the OS of metastatic CRC patients. Our study showed that there were significant associations between cytokine expression and prognosis of the patients with metastatic CRC. The CBPC that we developed includes multiple circulating cytokines and may serve as a novel screening tool for identifying metastatic CRC patients with a high risk of short OS. These high-risk individuals may also be suitable for cytokine-targeted therapies.Colorectal cancer (CRC) is characterized by a wide spectrum of microvascular and immunological abnormalities, a high rate of metastasis and a poor prognosis. [1][2][3][4] It is the third most common cancer and the third most common cause of cancer-related deaths worldwide. [5][6][7] The highly vascularized tumor composition in CRC has been reported to correlate with the local tumor invasion and distant metastasis, and anti-angiogenic therapy has been able to improve survival in patients with metastatic colorectal cancer. [8][9][10][11][12] Many cytokines have recently been reported to function as more than just attractants for inflammatory leukocytes. Accumulating evidence suggests that some cytokines and their receptors act as key regulators of the tumor microenvironment and are involved in many pathological entities ranging from inflammatory bowel disease to carcinogenic processes, such as autonomous growth signaling, influencing tumor growth, invasion and metastasis. [13][14][15] A variety of cells can secrete cytokines, including fibroblasts, endothelial cells, epithelial cells and macrophages, as well as cancer cells. Some host-derived cytokines have been reported to suppress tumor formation by regulating the immunological responses. 13,16 Conversely, some other cytokines and their receptors have