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Metastatic forms of cancers remain the main cause of death in cancer patients. In this study, we demonstrate that directing a sustained antibody response towards the homotypic binding function of CEA interferes with the implantation and development of tumor foci in CEA-expressing transgenic (CEA.Tg) mice. Specifically, vaccinating CEA.Tg mice with a recombinant, altered self-form of the CEA Ig V-like N domain led to the production of circulating IgG1 and IgG2a antibodies that inhibited CEAmediated adhesion of murine carcinoma expressing CEA (MC38.CEA) and mediated antibody-dependent lysis of tumor cells. Moreover, vaccinated CEA.Tg mice were resistant to the development of tumor nodules in the lungs and the peritoneal cavity, suggesting that mounting a focused antibody response to the CEA N domain may represent a simple therapeutic strategy to control the establishment of metastatic foci in cancer patients.There remains a strong need to develop therapies aimed at blocking or preventing the formation of metastatic tumor foci in cancer patients, in light of the fact that most cancer deaths are accounted for by patients with metastatic disease. Aberrantly expressed surface antigens, involved in intercellular adhesion, represent suitable targets for developing antiadhesive or antiaggregative therapies. One such surface marker is the carcinoembryonic antigen (CEA, CEACAM5 and CD66e), a GPI-linked glycoprotein linked to cell transformation and metastasis. CEA is frequently over-expressed on epithelial carcinomas of the intestinal and respiratory tracts, as well as cancers of the breast, pancreas, stomach and ovary. [1][2][3][4][5] From a clinical perspective, high preoperative serum concentrations of CEA correlate with metastasis, treatment failure and poor overall prognosis.6-10 Specifically, a recent prospective study of CEA levels in the serum of 2,062 breast cancer patients has revealed that a CEA level >7.5 lg/L is associated with a high probability of subclinical metastases and a significant reduction in disease free and overall survival rates. 11The association of CEA with cancer progression has led to its use as an immunogen in designing anticancer vaccines. 2,5 Mechanistically, the intercellular homophilic binding property of CEA correlates with cancer invasion and metastasis. 5,[12][13][14] CEA is composed of seven extracellular Ig-like domains