To determine whether circulating tumor‐reactive T cells are present in melanoma patients, unstimulated T cells from peripheral blood were tested for recognition of HLA‐A2‐ or HLA‐A1‐matched melanoma cell lines using the ELISPOT assay. Eleven out of 19 patients with metastatic melanoma had a T‐cell response with up to 0.81%, 0.78%, 0.53%, 0.12%, 0.10%, 0.09%, 0.07%, 0.06%, 0.06%, 0.04%, and 0.04% of peripheral blood mononuclear cells (PBMC) secreting IFNγ upon exposure to various HLA‐A2‐ or HLA‐A1‐matched melanoma cell lines. These T‐cell responses were mediated by CD8+ T cells and could specifically be blocked by an anti‐HLA‐A2 antibody in HLA‐A2‐positive patients. Separation experiments performed in one melanoma patient showed tumor‐reactive T cells in both the CD8+ effector T cell (CD45RA+/IFNγ+) as well as the CD8+ memory T‐cell compartment (CD45RO+/IFNγ+). In 3 out of 5 patients, in whom autologous cell lines were available, similar frequencies of T cells in response to HLA‐A1‐ or HLA‐A2‐matched allogeneic and autologous tumor cells were observed, while 2 patients had a T‐cell response restricted to either the autologous or the allogeneic cell lines. These results give evidence for the presence of tumor‐reactive CD8+ T cells in more than half of melanoma patients tested. Although some of these patients have clinical evidence for an immunological‐mediated tumor control, several patients have growing tumors suggesting presence of escape mechanisms. Int. J. Cancer 87:659–664, 2000. © 2000 Wiley‐Liss, Inc.