Background: EMT is a phenotypic description of cancer cells that include loss of cell adhesion, increased motility, invasion, and chemoresistance. EMT gene signature is a poor prognostic feature in colon cancer. Circulating markers to decipher the EMT signature in colorectal cancer patients (CRC pts) would therefore be of clinical relevance. Studies have shown that miR-21, IL-6 and IL-8 have been associated with EMT in cancer cells in vitro and their expression has been shown to be highly correlated in primary colon cancer tissue Methods: Plasma samples were obtained from two mCRC cohorts: 120 pts with unresectable metastases, and 91 pts who subsequently underwent partial hepatectomy with curative intent. Circulating levels of IL-6, IL-8 and miR-21 (normalized by miR-16) were measured, and dichotomized using previously published cutoffs. Pts with high levels of ≥2 of 3 EMT markers were categorized as having an EMT phenotype. Survival analysis was by log-rank and proportional hazard. Results: As previously seen in colon tissue, miR-21, IL-6 and IL-8 expression were correlated in plasma samples (P<0.001) and individually associated with shorter overall survival (P<0.05). The EMT phenotype, present in 44% of both cohorts, was a strong predictor of poor overall survival in the unresectable cohort (HR 2.6, 95% CI 1.6 to 4.1, median OS 15.5 mo v 27.1 mo, P<0.001) as well as in the validation resectable cohort(HR 3.8, 95% CI 1.9 to 7.7, median OS 41.5 mo vs 81.9 mo, P<0.001). This effect was sustained in a multivariate analysis after adjustment for tumor volume and clinical characteristics (HR 1.92, P=0.009 in unresectable cohort and HR 3.53, p=0.002 in hepatectomy cohort). The EMT phenotype was also predictive of shorter progression-free survival (HR 2.2, 15.8 mo vs 7.8 mo, P=0.02) and relapse-free survival (HR 2.1, 18.4 mo vs 31.4 mo, P=0.01) in the two respective cohorts, consistent with prior preclinical data correlating EMT with chemoresistance Conclusions: As surrogates of EMT, circulating levels of miR-21, IL-6 and IL-8 are co-expressed in plasma of mCRC pts and can be used to predict overall survival and benefit from chemotherapy. This finding highlights the clinical relevance of EMT in colon cancer biology