To investigate the possibility that Fas-based immune regulation and Fas-based T cell-mediated cytotoxicity (F-CMC) are causally related, we explored the latter in activated lymphocyte populations. These were shown to contain effector cells exerting cytotoxicity via an F-CMC mechanism which could be differentially triggered by PMA and ionomycin. F-CMC operated in trans, requiring an lpr (Fas) product on target cells and a gld product on effector cells. Activated lymphocyte populations were also shown to contain F-CMC target cells. Activated lymphocyte populations thus contained both effector and target F-CMC cells, which could lyse each other. Fas-based cytotoxicity can thus lead to the lysis of syngeneic activated lymphocytes, consistent with the possibility of its participation in the down-regulation of immune responses, and more generally offering a model of socially controlled, direct membrane-mediated cell death.