Few robust biomarkers are available for distant metastatic colorectal cancer (CRC) patients. Aberrant high expression of CDH3 has been reported in advanced CRC patients, but the value of CDH3 as a biomarker for the diagnosis and prognosis of distant metastatic CRC patients remains to be evaluated. In this study, we explored the serum levels of CDH3 in different stages of CRC patients and sought to determine whether serum CDH3 serves as an independent biomarker for distant metastatic CRC patients. We analyzed the serum CDH3 levels by ELISA in a cohort of CRCs (n=96) and normal controls (n=28). We compared the serum CDH3 levels between normal controls and different stages of CRCs. As a potential diagnostic marker of distant metastatic CRC, the specificity and sensitivity of serum CDH3 were evaluated. Multivariate analysis was also performed to determine whether serum CDH3 was an independent risk factor. Moreover, the changes of serum CDH3 levels were monitored and analyzed before and after palliative chemotherapy. Serum levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA were significantly elevated in distant metastatic CRCs. CA24-2 (r=0.24, P=0.01), CA19-9 (r=0.20, P=0.03), CA72-4 (r=0.64, P<0.0001), and CEA (r=0.31, P=0.0012) all had a certain correlation with CDH3. After three cycles of palliative chemotherapy, levels of CDH3, CA24-2, CA19-9, CA72-4, and CEA of partial response CRCs were reduced to 38.8% (95% confidence interval [CI]: 30.95%-53.77%), 57.73% (95% CI: 2.085%-73.83%), 50.33% (95% CI: 9.935%-79.42%), 74.74% (95% CI: 25.21%-88.00%), and 59.16% (95% CI: 12.65%-83.56%) of baseline, respectively. The areas under the receiver operating characteristic curves of CDH3, CA24-2, CA19-9, CA72-4, and CEA with chemotherapy response were 0.900, 0.597, 0.635, 0.608, and 0.507, respectively. Serum CDH3 is an effective serum biomarker for the diagnosis of distant metastatic CRCs and monitoring response to palliative chemotherapy in distant metastatic CRCs.