The nuclear factor κ light chain enhancer of activated B cells (NFκB) is constitutively active in most cancers, controlling multiple cellular processes including proliferation, invasion and resistance to therapy. NFκB is primarily regulated through the association with inhibitory proteins that are known as inhibitors of NFκB (IκBs). Increased NFκB activity in tumor cells has been correlated with decrease stability of IκB proteins, in particular IκBα. In responso to a large number of stimuli, IκB proteins are degraded by the proteasome. Cytotoxic T lymphocytes (CTLs) recognize HLA-restricted antigenic peptides that are generated by proteasomal degradation in target cells. In the present study, we demonstrate the presence of naturally occurring IκBα -specific T cells in the peripheral blood of patients suffering from several unrelated tumor types, i.e., breast cancer, malignant melanoma and renal cell carcinoma, but not of healthy controls. Furthermore, we show that such IBα-specific T cells are granzyme B-releasing, cytotoxic cells. Hence, the increased proteasomal degradation of IκBα in cancer induces IκBα-specific CTLs.