Background: Currently, blood markers are noninvasive methods for the diagnosis of patients with colorectal cancer (CRC). We evaluated four biomarkers (Carcinoembryonic antigen (CEA), carbohydrate antigen 19.9 (CA19.9), collagen III, and metalloproteinase 1 (MMP-1)) and their combination as a substitute method to enhance diagnosis of CRC. Subjects and methods: one hundred ninety-five patients who had undergone colonoscopy examination were included in the study (135 CRC and 60 benign growths). Also, 45 healthy individuals were included.  Multivariate discriminant analysis (MDA) and area under the receiver operating characteristic curve (AUC) were applied for evaluating the diagnostic power of single and their combination. Results:  levels of collagen III, CEA, and CA 19.9 increased while MMP-1 decreased with the progression of CRC  (stages, positive lymph node invasion, distant organ metastasis, and high grades)  with a significant difference (P P < 0.0001). Combination of MMP-1, CEA, CA 19-9, and Collagen III yielded MC3 index had diagnostic power greater than every single marker could achieve alone. When differentiating colon cancer from benign growth, the AUC of MC3 index was 0.91 yielded 85.2% sensitivity and 86.7% specificity. Moreover, the MC3 index for patients with late stages, lymph node invasion, organ metastasis, and high-grade had AUC = 0.81, 0.82, 0.80, and 0.80 higher than CEA and CA19.9.Conclusion:  MC3 index is can be used as an effective index for early detection of CRC.