Colorectal cancer is the most common cancer of the gastrointestinal system and has a marked preference to metastasize to distant organs. In this study, we investigated whether levels of circulating serum pro-angiogenic cytokine such as chemokine (C-X-C motif) ligand 1 (melanoma growth-stimulating activity, alpha; CXCL1) and vascular endothelial growth factor (VEGF) have a role in favoring the colonization of metastatic cells at preferential sites and determined their prognostic significance in a cohort of 103 patients with metastatic colorectal cancer. Importantly, we found that the presence of elevated circulating levels of VEGF and CXCL1 are predictive of liver and lung metastasis, respectively. Moreover, the presence of a high serum VEGF level represents a negative prognostic factor for patients with liver metastases, with a worse prognosis than patients with lung metastasis. This suggests an additional role for circulating cytokines as a predictive tool for cancer prognosis and diagnosis, as well as for assessment of tumor sensitivity to anticancer therapy.