Tumor cells express tumor‐associated antigens (TAAs), which can serve as targets for the immune system. However, the majority of TAAs are overexpressed products of normal cellular genes; as such, self‐tolerance mechanisms have hindered their use for the induction of effective antitumor responses. One such normal self‐protein is the growth factor receptor Her‐2/neu, which is overexpressed in 25–35% of all mammary carcinomas in humans. In previous studies, we have demonstrated that Her‐2/neu mice are functionally tolerant to neu antigens and contain only a low avidity T‐cell repertoire to neu antigens. However, this residual low‐avidity T‐cell repertoire has antitumor activity. In this study, we compared the immune responses of Her‐2/neu mice immunized with dendritic cells (DCs) pulsed with soluble neu protein or with apoptotic tumor cells. Analysis of the antitumor response shows that Her‐2/neu mice vaccinated with DCs pulsed with Her‐2/neu antigens retard tumor growth; however, vaccination with DCs pulsed with apoptotic tumor cells induces a stronger antitumor effect. Administration of multiple immunizations in combination with the costimulatory agonist anti‐OX40 or anti‐4‐1BB MAb significantly enhanced the immune responses in these mice, resulting in complete tumor rejection if the tumor burden was small and substantial tumor reduction with a larger tumor burden. These results have important implications for the design of tumor vaccination strategies, suggesting that the use of vaccines that stimulate a broad immune response in combination with costimulatory molecules as immunomodulators could significantly improve the antitumor immune response in tolerant hosts. © 2005 Wiley‐Liss, Inc.