HLA-class I-specific natural killer cell receptors (HNKR) have been described to significantly interfere with both specific and non-specific functional activities of T lymphocytes. Despite the clear evidences obtained in T cells derived from peripheral blood, little is known about the activity of HNKR expressed in tumor infiltrating lymphocytes. For this reason, we have studied T lymphocytes derived from advanced non small cell lung cancers (NSCLC). The population of T cells expressing the HNKR + phenotype was rare both in NSCLC-associated lymphocytes and in the peripheral blood. The two populations were clearly oligoclonal, as shown by the analysis of T cell receptor repertoire. Interestingly, while HNKR + T cells derived from the peripheral blood belonged to the CD45R0 phenotype, the large majority of HNKR + T cells in TIL were CD45RA. Functionally, all HNKR + T cells displayed a cytolytic activity against allogeneic NSCLC. Autologous NSCLC, tested in a single patient, was lysed efficiently by HNKR + T cells, thus suggesting that at least in this model, the presence of HNKR did not significantly interfere with the functional capacity of effector cells.