A subset of circulating T cells (CD8(+)CD45RO(-)CD27(-)) with a naïve phenotype, but mediating effector function, is considered to play an important role in host antitumour defence. To investigate the attributes of these effector T cells in patients with squamous cell carcinoma (SCC) of the head and neck cancer, venous blood was obtained from 39 individuals with cancer and 45 normal controls (NC). Peripheral blood mononuclear cells were isolated, stained with labelled monoclonal antibodies specific for CD8, CD45RO, CD45RA, CD62L, CD27, TCR-zeta as well as isotype controls and examined by multicolour flow cytometry. Annexin V binding to CD8(+) T cells and PMA/ionomycin-induced IFN-gamma expression were also evaluated in patients and NC. The proportions of CD45RA(+)CD45RO(-) (naïve) and CD45RA(-)CD45RO(+) (memory) cells were found to be comparable within the CD8(+) T-cell subset. However, relative to NC, the frequency of effector CD8(+)CD45RO(-)CD27(-) cells was strikingly increased in all SCC patients regardless of the disease status (P=0.0003). The proportion of these cells was found to increase with age in both patients and NC. In NC, stimulated IFN-gamma expression was largely restricted to CD8(+)CD45RO(-)CD27(+) cells, while in patients CD8(+)CD45RO(-)CD27(-) expressed IFN-gamma after ex vivo stimulation. Expression of the TCR-associated zeta chain was decreased or absent in freshly isolated CD8(+)CD45RO(-)CD27(-) T cells in patients (P0.0001). Annexin V was found to bind to a higher proportion of circulating CD8(+) T cells in patients than NC (P0.006), and significantly more Annexin V(+) T cells were present in the effector (P0.0059) than the naïve subset within the CD8(+)CD45RO(-) compartment. The data indicate that the expanded CD8(+)CD45RO(-)CD27(-) T cells, which contain precursors of IFN-gamma-producing T cells, are zeta-negative and sensitive to apoptosis in the circulation of patients with HNC.