Background: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths, as about half of cases develop incurable metastatic disease. Recent studies have shown circulating tumor DNA (ctDNA) markers reflect disease burden and responses to neoadjuvant therapy in metastatic CRC more accurately than carcinoembryonic antigen (CEA). We aimed to determine if a semi-quantitative evaluation of the methylated SEPTIN9 (mSEPT9) ctDNA marker, used in a CRC screening test, is capable of predicting progression free survival (PFS) and overall survival (OS) in a longitudinal cohort of metastatic CRC cases. Methods: A longitudinal cohort of 70 CRC cases who presented with stage IV disease, or experienced recurrent disease, was prospectively assembled from patients undergoing treatment at Cedars-Sinai Medical Center. Blood samples were drawn either prior to, or within 2 weeks following, treatment initiation, and 1-2 monthly thereafter for two years or until death. mSEPT9 ctDNA levels were measured in 1 mL plasma using a modified Epi-proColon V2.0 (Epigenomics) protocol. Univariate and multivariate analyses of clinical endpoints, PFS and OS, were conducted using a Cox regression model with CEA and mSEPT9 ctDNA as time-dependent covariates, with and without adjustments for multiple confounding factors (sex, age, race, organ of metastasis, neo- and adjuvant chemotherapy, immunotherapy, surgery, mismatch repair, KRAS and BRAF mutation status). Results: In univariate analysis, higher level of ctDNA, peritoneal metastasis, gynecologic metastasis, and additional liver metastasis, were associated with poor PFS. Elevated CEA was not associated with PFS either as a continuous variable or as a categorical variable (threshold 10ng/mL). In multivariable analysis, higher level of ctDNA (HR: 1.41; 95% CI: 1.17-1.71; P< 0.001) remained associated with poor PFS after adjusting for adjuvant chemotherapy and peritoneal metastasis. CEA remained not associated with PFS. In univariate analyses, high level of CEA, high level of mSEPT9 ctDNA, neoadjuvant chemotherapy, male sex, and peritoneal metastasis were associated with poor OS. In multivariable analysis, higher level of CEA (HR: 1.63; 95% CI: 1.12-2.36; P= 0.011) and mSEPT9 ctDNA (HR: 1.50; 95% CI: 1.22-1.84; P< 0.001) remained associated with poor OS after adjusting for sex and peritoneal metastasis. Conclusions: Semi-quantification of the single ctDNA marker, mSEPT9, a prevalent biomarker of CRC, was an independent predictor of PFS whereas CEA was not. High levels of both CEA and mSEPT9 ctDNA were independent predictors of OS, showing that mSEPT9 ctDNA added value to CEA in evaluation of OS. The mSEPT9 ctDNA test is rapid turn-around and easy to perform in molecular diagnostic pathology laboratories, thus may serve as a valuable adjunct to CEA for frequent testing in the setting of metastatic CRC.