MHC I–restricted epitopes of chicken ovalbumin (OVA) were originally identified using CD8(+) T cells as probes. Here, using bioinformatics tools, we identify 4 additional epitopes in OVA in addition to a cryptic epitope. Each additional epitope is presented in vivo, as deduced from the lack of CD8(+) T cell response to it in OVA-transgenic mice. In addition, CD8 responses to the previously known epitopes and those identified in this study are examined in C57BL/6J mice exposed to the OVA-expressing tumor E.G7 in several ways. No responses to any epitope, including SIINFEKL, are detected in mice with growing E.G7 or mice immunized with the tumor. Only in E.G7-bearing mice treated with an anti–CTLA-4 antibody, which depletes tumor-infiltrating regulatory T cells, are CD8 responses to SIINFEKL and the epitope EKYNLTSVL identified in this study detected. Finally, all epitopes fail to treat mice with preexisting tumors. These observations force an important reconsideration of the common assumptions about the therapeutic value of neoepitopes detected by CD8 responses in tumor-bearing hosts.