CD276 can discriminate between tumor derived and normal CECs (circulating endothelial cells). We evaluated whether CD276+CEC is a clinically relevant biomarker to predict response to palliative systemic therapy in patients with metastatic colorectal cancer (mCRC). Samples were prospectively collected from patients with mCRC enrolled in the ORCHESTRA trial (NCT01792934). At baseline and after three cycles of 5-fluorouracil/leucovorin and oxaliplatin ± bevacizumab, CECs were measured by flowcytometry (CD34+CD45negCD146+DNA+; and CD276+). A clinically relevant cut-off value of (CD276+)CECs was determined as 100% sensitivity (and 80% specificity in 95% confidence interval) identifying patients with progressive disease within 6 months. There were 182 baseline samples and 133 follow up samples available for analysis. CEC and CD276+CEC counts significantly increased during treatment from 48 to 90 CEC/4 mL (p = 0.00) and from 14 to 33 CD276+CEC/4 mL (p = 0.00) at baseline and at first evaluation, respectively. CEC and CD276+CEC counts were not predictive for poor response (area under the curve (AUC) 0.53 for CEC and AUC 0.52 for CD276+CEC). Despite numerical changes during therapy, CEC and CD276+CEC counts do not adequately predict poor response to first line palliative systemic therapy in patients with mCRC.