Several reports suggest that natural killer (NK) cells recognize the transferrin receptor (TFR) as a target for killing, and that natural cytotoxicity may be involved in the control of stem cell proliferation in bone-marrow. This study tested whether NK-cell recognition of the TFR on activated lymphocytes plays a role in the control of peripheral immune responses. Six lymphoid lines were created from a single individual, and used as targets for cytotoxicity assays, using either peripheral blood mononuclear cells, or mixed lymphocyte reaction (MLR)-derived effectors. The cells responsible for killing were predominantly Leu-11+Leu-7+ NK cells, though CD3+ cells accounted for about 25% of cytotoxicity from MLR. No correlation was observed between TFR density and NK susceptibility when using all six cell lines. Specifically increasing the density of TFR on a single cell line failed to increase susceptibility to NK, suggesting that the TFR does not act as a major target for natural cytotoxicity directed at lymphoid cells. Furthermore, the relatively low levels of killing observed indicate that activated NK populations that accumulate at sites of immune response are unlikely to play a direct immunoregulatory role.