Successful tumor immunotherapy with peptides requires the induction of cytotoxic T lymphocytes (CTLs) rather than antibodies. Mice immunized with mannan conjugated to MUC1, a peptide found in large amounts in breast cancer, develop CTL responses. In contrast, immunized patients produce high antibodies with poor CTL responses to MUC1. Here, we provide evidence that this "switch" in the immune response is due to the fact that antibodies against the Gal alpha(1,3)Gal epitope, which are normally present in humans but not mice, cross-react with MUC1 peptides. In particular, mice that lack the gene for the epitope (and that produce anti-Gal antibodies) (Gal-/- mice) are like humans in their response to MUC1 immunization in that they develop antibody rather than CTL responses. After we exposed macrophages from Gal-/- mice in vitro to MUC1, in the absence of Gal antibody, and adoptively transferred them into the mice, Gal-/- mice produced a predominantly CTL response. The findings are of relevance for immunotherapy studies in humans and emphasize the differences seen in preclinical testing in rodents before clinical trials.