Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Consequently, new diagnostic and therapeutic approaches are being investigated including the serum levels of cytokines and other molecules, although the results are often inconclusive. Thus, the present study aimed to determine whether serum level of cytokines, cell adhesion molecules or matrix metalloproteinases (MMPs), alone or in combination, may contribute to the non-invasive diagnosis of CRC. The serum levels of nine cytokines [ILs; IL-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-22 and IL-33, and interferon (IFN)-γ], two cell adhesion molecules (intercellular adhesion molecule-1 and P-selectin) and an MMP-7 were measured by ELISA in 33 patients with CRC and 35 healthy controls. Combined capacity of all molecules to detect the presence of CRC was assessed by logistic regression. Molecules and molecule combinations were tested for all stages and tumor grades. A significant increase was identified for IL-8 in patients compared with healthy controls; IL-10 was found to be significantly decreased. The biomarker potential of each significantly modified molecule was tested: IL-8 had a sensitivity of 0.865, a specificity of 0.600 and an area under the curve (AUC) of 0.777; for IL-10, sensitivity was 0.65, specificity was 0.69, with an AUC of 0.689. Logistic regression determined the best discriminative potential between patients and control groups for the combination IL-4 + IL-6 + IL-8 + IFN-γ, with 0.97 sensitivity and 0.58 specificity. For the early stages of CRC, the combination IL-6 + IL-8 + IL-22 showed good performance. It was concluded that increased IL-8 had potential as single biomarker in CRC. Cytokine combinations are superior to single cytokine analysis in showing the presence of CRC.