BACKGROUND: In cancer, tumor escape from the host immune system includes apoptosis of circulating CD3(+)CD8(+) effector T lymphocytes. Here, we compare sensitivity to apoptosis of virus- with tumor-specific circulating CD8(+) T cells in patients with head and neck cancer. METHODS: Wild-type p53 peptide-specific (p53(264-272) and p53(149-157)) and viral peptide-specific (EBV BMLF(259-267) and CMVpp65(495-503)) tetramers were used to measure the frequency of reactive T cells by flow cytometry. Annexin V (ANX) binding to circulating 7-amino-actinomycin D-negative but tetramer(+)CD8(+) T cells in PBMC obtained from 21 patients with head and neck cancer and 11 normal controls (NC) was evaluated. RESULTS: In patients with head and neck cancer, a higher percentage of tetramer(+)CD8(+) than tetramer(-)CD8(+) T cells bound ANX (p < .023-.005). Although most tumor-epitope(+)CD8(+) T cells bound ANX, lower percentages of virus-specific CD8(+) T cells were ANX(+) in the same patients. CONCLUSIONS: Preferential demise of circulating tumor-specific CD8(+) T cells and their paucity in head and neck cancer contribute to tumor escape.