The majority of tumor-associated antigens are aberrantly expressed or overexpressed normal gene products. Therefore, mechanisms responsible for self tolerance dampen immune responses against these antigens. To evaluate the effect that tolerance has on the immune responses against tumor antigens, we characterized the CD8+ T cell responses in neu mice. T cell responses against the A2.1/neu p369-377 and p773-782 peptides were evaluated in neu mice that were crossed with A2.1/Kb transgenic mice (A2 x neu). Tetramer binding and cytotoxic activity demonstrate that, compared to CTL from A2.1/Kb x FVB wild-type mice (A2 x FVB), CD8+ T cells from A2 x neu mice were of lower avidity for the peptides. Despite the fact that A2 x neu mice are tolerant, multiple immunizations with DC pulsed with the p369-377 or p773-782 peptides in the presence of IL-2 retarded tumor growth in A2 x neu mice, and immunizations in combination with the anti-OX40 mAb further enhanced the antitumor response. Taken together, these data indicate that low-avidity T cells for neu antigens persisting in A2 x neu mice have the capacity to develop antitumor responses as long as they are provided with efficient costimulation. These results underscore the potential role of low-avidity T cells in antitumor immunity and may offer an important component for vaccination immunotherapies.