Background: CD66e (Carcinoembryonic antigen, CEA) affects tumorigenesis by enhancing tumor cell survival and by inducing tumor-angiogenesis. This study aimed to evaluate baseline CD66e serum levels as response predictor to bevacizumab-based therapies in patients with metastatic colorectal cancer (mCRC). Methods: 298 patients with mCRC and first-line treatment were analyzed. 169 mCRC received bevacizumab plus chemotherapy and 129 patients with mCRC treated with cetuximab (KRAS w.t.) and identical chemotherapy (FOLFOX6 or FOLFIRI). Disease control (DC), progression-free survival (PFS) as well as overall survival (OS) were assessed and related to baseline CD66e-serum levels. Patients with basal CD66e-serum levels below the statistical median of 26.8 ng/ml (group I) were compared with patients with higher CD66e levels (group II). Results: Baseline CD66e serum levels inversely correlated with therapeutic response in patients receiving bevacizumab-based treatment (chi square i<0.005: OR=0.579, 95% C.I. 0.422, 0.795; p<0.001), inversely correlated with median PFS leading to a median PFS benefit of 2.1 month for patients in group I when compared with group II (p<0.05), as well as inversely correlated with median OS (37.5 month vs. 21.4 month, p<0.05). In an independent cohort of 129 patients treated with cetuximab-based therapy, no association of therapeutic response or PFS with CD66e serum levels was found (p>0.05). Conclusions: These data give first evidence of CD66e as a predictive biomarker for the efficacy of first-line bevacizumab-based therapy in patients with mCRC.