Carcinoembryonic antigen (CEA) is intensively studied as a potential target for immunotherapy of colorectal cancers. Although overexpressed by tumors, CEA is also expressed in normal tissues, raising questions about the feasibility and safety of CEA-targeted immunotherapy. We investigated these issues in transgenic mice in which the expression of human CEA in normal tissues closely resembles that in man. Our data show that the T-cell response against CEA in these mice is blunted by both thymic and peripheral tolerance. Consequently, effective tumor targeting is only achieved by adoptive transfer of T cells from nontolerant donors in combination with interventions that eliminate peripheral immune regulatory mechanisms. However, such treatments can result in severe intestinal autoimmune pathology associated with weight loss and mortality. Interestingly, preconditioning of recipient mice by depletion of T-regulatory cells results in immune-mediated tumor control in the absence of toxicity. In this setting, CEA-specific T-cell responses are lower than those induced by toxic regimens and accompanied by additional T-cell responses against non-self antigen. These findings illustrate the importance of testing adoptive immunotherapies targeting self antigens such as CEA in preclinical in vivo models and show that the choice of immune intervention regimen critically determines the balance between therapeutic efficacy and toxicity. [Cancer Res 2008;68(20):8446–55]