In this study, we examined the function of cellular apoptosis regulator Bid using genetically deficient murine embryo fibroblasts (MEFs) and mice. We found that while Bid is dispensable for reovirus replication in cell culture, its function is required for reovirus-induced apoptosis. Blockade of NF-kB signaling, which diminishes apoptosis induction by reovirus [8, 28] , prevents cleavage of Bid. In comparison to wild-type mice, Bid-deficient mice display diminished susceptibility to reovirus-induced CNS disease following either peroral (PO) or intracranial (IC) inoculation. Attenuated reovirus virulence in the absence of Bid is associated with decreased reovirus replication in the murine CNS. These results define an important role for Bid in virusinduced apoptosis and disease and illuminate Bid-dependent prodeath signaling as a viable target for antiviral therapy.