Using a murine transitional cell carcinoma tumor model, MB49, which naturally expresses the male antigen HY, we evaluated whether tumor ignorance as determined by lack of a systemic immune response could be overcome by immunization with vaccinia expressed tumor antigen and granulocyte macrophage colony-stimulating factor. Systemic tumor ignorance of MB49 was demonstrated by the lack of a splenic HY-specific CTL response in MB49-bearing female mice. In contrast, we demonstrated HY-specific CTL priming in the draining lymph nodes. MB49-bearing female B6 mice were immunized with VVHY+VVGMCSF intratumorally or in the contralateral flank. Intratumoral VVHY, VVGMCSF, and keyhole limpet hemocyanin (to produce CD4 help) generated splenic HY-specific CD8 CTLs, whereas immunization with the combination in the contralateral flank or single agents given intratumorally failed to yield a splenic response. Purified male T cells injected intratumorally, as a source of HY antigen, also generated a HY-specific response, whereas contralateral immunizations did not. These finding expand the understanding of tumor immunological ignorance and support intratumoral vaccination as a strategy for immunotherapy of established tumors.