Inhibitors of ICE-family proteases (caspases) block many examples of apoptotic cell death in vivo and in vitro, including multiple apoptotic stimuli for T lymphocytes. We have tested whether cell death induced by cytotoxic T lymphocytes was also blocked by caspase inhibitors. We found that the rapid apoptotic target cell death induced by Fas ligand-bearing CTL using the target Fas death pathway was efficiently blocked by caspase inhibitors. In contrast, target lysis induced by the CTL granule exocytosis pathway is not detectably blocked by such inhibitors, although the accompanying apoptotic nuclear damage is efficiently blocked. Thus caspase inhibitors prevent the hallmark phenotype of apoptosis without measurably affecting target cell death as evidenced by lysis.