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Telomerase is a ribonucleoprotein complex responsible for the maintenance of the length of the telomeres during cell division, which is active in germ-line cells as well as in the vast majority of tumors but not in most normal tissues. The wide expression of the human telomerase catalytic subunit (hTERT) in tumors makes it an interesting candidate vaccine for cancer. hTERT-derived peptide 540–548 (hTERT540) has been recently shown to be recognized in an HLA-A*0201-restricted fashion by T cell lines derived from peptide-stimulated peripheral blood mononuclear cells (PBMC) from healthy donors. As a first step to the inclusion of this peptide in immunotherapy clinical trials, it is crucial to assess hTERT540-specific T cell reactivity in cancer patients as wellas the ability of hTERT-specific CD8⁺ T lymphocytes to recognize and lyse hTERT-expressing target cells. Here, we have analyzed the CD8⁺ T cell response to peptide hTERT540 in HLA-A*0201 melanoma patients by using fluorescent HLA-A*0201/hTERT540 peptide tetramers. HLA-A*0201/hTERT540 tetramer⁺ CD8⁺ T cells were readily detected in peptide-stimulated PBMC from a significant proportion of patients and could be isolated by tetramer-guided cell sorting. hTERT540-specific CD8⁺ T cells were able to specifically recognize HLA-A*0201 cells either pulsed with peptide or transiently transfected with a minigene encoding the minimal epitope. In contrast, they failed to recognize hTERT-expressing HLA-A*0201⁺ target cells. Furthermore, in vitro proteasome digestion studies revealed inadequate hTERT processing. Altogether, these results raise questions on the use of hTERT540 peptide for cancer immunotherapy.