Data on the subject of cell-mediated cytotoxicity suggest that no single mechanism is likely to provide a satisfactory explanation of this process. Lytic pathways have been proposed that involve both the effector cell and the target cell as active participants. In this report we describe a system in which the target cell is rendered unable to participate in its own demise. Using sheep E derivatized with CD3 antibodies, we show that metabolic inhibition of SRBC by depleting intracellular ATP with iodoacetamide, or even conversion of SRBC to "ghosts" by hypotonic lysis and resealing, has no effect on cytolysis. In the presence of EGTA or cholera toxin, both of which inhibit CTL degranulation, there is a strong suppression of both serine esterase release and cytolysis. These data show clearly that in some situations CTL are able to lyse target cells without any active participation by the target cells themselves.