Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.