Glycoprotein tumor Ag MUC1 is overexpressed on the majority of epithelial adenocarcinomas. CTLs that recognize MUC1 and can kill tumor cells that express this molecule have been found in cancer patients, yet they are present in low frequency and unable to eradicate MUC1+ tumors. Patients also make anti-MUC1 Abs but predominantly of the IgM isotype reflecting the lack of effective MUC1-specific Th responses. Mice transgenic for the human MUC1 gene (MUC1-Tg) are similarly hyporesponsive to MUC1. We used a vaccine consisting of dendritic cells loaded with a long synthetic MUC1 peptide to investigate the fate and function of MUC1-specific CD4+ Th elicited in wild-type (WT) or MUC1-Tg mice or adoptively transferred from vaccinated WT mice. We show that hyporesponsiveness of MUC1-Tg mice to this vaccine is a result of insufficient expansion of Th cells, while at the same time their regulatory T cells are efficiently expanded to the same extent as in WT mice and exert a profound suppression on MUC1-specific B and T cell responses in vivo. Adoptive transfer of WT Th cells relieved this suppression and enhanced T and B cell responses to subsequent MUC1 immunization. Our data suggest that the balance between Th and regulatory T cells is a critical parameter that could be modulated to improve the response to cancer vaccines.