Background: Colorectal cancer (CRC) is the most common and treatable gastrointestinal (GI) cancer, yet it remains the second leading cause of cancer associated deaths globally. Cadherin-17 (CDH17) is a biomarker for GI cancers characterized by its overexpression in stomach, liver, and colorectal cancers but controlled expression in normal tissues from healthy adults. Although an improvement in the detection strategy of CDH17 is essential to apply it for large scale CRC screening. We have developed a novel diagnostic immunoassay using a panel of highly specific antibodies (PCT/US2019/032752) that unveiled CDH17 as a potential diagnostic maker with high detection sensitivity and specificity in CRC. Methods: The study recruited 150 patients (Retrospective specimens - 50 colorectal adenomas and 100 colorectal cancer) and 50 asymptomatic 18-80 years old blood donors (prospective specimens). CDH17 expression levels were measured within the individual blood-plasma samples using an enzyme-linked immunoassay. Results: The novel CDH17 diagnostic assay showed a wide operating dynamic range extending from 90ng to a lower limit of detection at 123pg. Using the assay, we observed a progressive and a significant increase in the plasma CDH17 concentration from the asymptomatic individuals to the colorectal adenoma group, while the CRC patients showed the highest expression of the circulating protein (median: 2.5ng/mL vs 4.5ng/mL vs 8.0ng/mL, P<0.0001). Within the CRC group, a higher CDH17 expression was associated with advanced tumor invasion, occurrence of nodal or distant metastases, as well as a clinical presentation of an advanced stage disease. The diagnostic power of the assay in terms of ROC AUC values was higher than 0.9 with an overall sensitivity of 82% that extended to 100% for metastatic CRC, while the specificity was at 94% for all stages combined (P<0.0001). Plasma CDH17 outperformed the clinically applied CEA and CA19-9 markers in differentiating the CRC patients from the asymptomatic population. Conclusions: The CDH17 immunoassay is potentially a diagnostics tool aid for the detection of CDH17 within blood samples prompting the early diagnosis of CRC.