The murine mammary adenocarcinoma cell line TS/A is a highly malignant MHC class II‐negative tumor. We show that transfection of TS/A cells with the MHC class II transactivator CIITA renders them MHC class II‐positive and highly immunogenic in vivo. These cells were fully rejected by 51% of syngeneic recipients and had a significantly lower growth rate in the remaining 49% of animals. This directly correlated to the amount of MHC class II molecules expressed in the transfected tumor. Tumor rejecting animals were protected against rechallenge with the parental TS/A tumor. The rejection required CD4⁺ and CD8⁺ T cells. CD4⁺ T cells were fundamental in the priming phase of the antitumor response. CTL‐specific for a peptide of the envelope gp70 of an endogenous ecotropic retrovirus were identified and explained the specificity of the effector mechanism of rejection against the TS/A and the antigenically related C26 carcinoma cells but not against the unrelated gp70‐negative syngeneic fibrosarcoma F1F cells. This is the first example of successful tumor vaccination by genetic transfer of CIITA. These results open the way to a possible use of CIITA for increasing both the inducing and the effector phase of the antitumor immune response.