Caspases are cell death cysteine proteases that are activated upon the induction of the apoptotic program and cleave target proteins in a sequence-specific manner to promote cell death. Recently, Barkett et al. (Barkett, M., Xue, D., Horvitz, H. R., and Gilmore, T. D. (1997) J. Biol. Chem. 272, 29419-29422) have shown that IkappaBalpha, the inhibitory subunit of the transcription factor NF-kappaB, can be cleaved by caspase-3 in vitro at a site that potentially produces a dominant inhibitory form of IkappaBalpha. The involvement of NF-kappaB in the inhibition of cell death led us to ask whether apoptotic stimuli would induce the caspase-mediated cleavage of IkappaBalpha in vivo. In this study, we show that apoptosis leads to the caspase-mediated amino-terminal truncation of IkappaBalpha (DeltaN-IkappaBalpha). Our data show that DeltaN-IkappaBalpha can bind NF-kappaB, suppress NF-kappaB activation, and sensitize cells to death. Since activated NF-kappaB plays a role in the inhibition of cell death, these data suggest that caspase-mediated cleavage of IkappaBalpha may be a mechanism to suppress NF-kappaB and its associated antiapoptotic activity.