Early steps in reovirus replication elicit apoptosis via a signaling pathway dependent on NF-kB [4, 7, 8, 14, 15] . It is not understood how virus-induced NF-kB activation leads to cell death. In this study, we evaluated the function and regulation of Bid in apoptosis caused by reovirus. We found that although Bid is dispensable for reovirus replication in cell culture, it is required for the induction of apoptotic cell death following reovirus infection. In this context, Bid is converted to its active, proapoptotic form, tBid, in an NF-kB-dependent manner. Generation of tBid in reovirus-infected cells requires signaling via TRAIL-R and caspase-8. These findings indicate that NF-kB signaling following reovirus infection results in activation of the extrinsic apoptotic pathway. In turn, the extrinsic apoptotic pathway evokes the mitochondrial apoptotic cascade via cleavage-induced activation of Bid. Together, these events culminate in the induction of apoptotic cell death.