Lymphoma cells are malignant cells of the T- or B-cell lineage which often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self-antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC expressing ovalbumin induced strong cytotoxic T-cell immunity which led to clearance of E.G7- OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self- antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25+ T cells (regulatory T cells, Treg) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self-antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25+ Treg is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help towards stimulation of Treg.