Recent demonstrations of the specific immune prevention of mammary cancer in female BALB/c mice transgenic for the rat Her-2/neu oncogene (BALB-neuT) have resulted in reconsideration of the immune mechanisms that inhibit tumor growth. All the mammary glands of these mice progress asynchronously, but consistently, from hyperplasia to invasive carcinoma. Overexpression of the oncogene product p185neu is first evident in the rudimentary glands of 3-week-old mice. Carcinogenesis is prevented by vaccination with plasmids coding for the extracellular and transmembrane domains of this p185neu, or with allogeneic cells expressing p185neu on their membrane, plus the systemic administration of IL-12. This inhibition is the outcome of a delayed-type hypersensitivity specific for p185neu and the production of anti-p185neu antibodies that restrain the proliferation of tumor cells by stripping p185neu from their membrane, whereas cytotoxic T lymphocytes seem devoid of a major role.