IFNs play critical roles in host defense by modulating the expression of various genes via signal transducer and activator of transcription factors. We show that IFNα/β activates another important transcription factor, NF-κB. DNA-binding activity of NF-κB was induced by multiple type 1 IFNs and was promoted by IFN in a diverse group of human, monkey, rat, and murine cells. Human IFN promoted NF-κB activation in murine cells that express the human IFNα/β receptor-1 signal-transducing chain of the type 1 IFN receptor. IFN promotes inhibitor of kappa B α (IκBα) serine phosphorylation and degradation, and stimulates NF-κB DNA-binding and transcriptional activity. Importantly, IFN promotes cell survival by protecting cells against a variety of proapoptotic stimuli, such as virus infection and antibody-mediated crosslinking. Expression of superrepressor forms of IκBα, besides inhibiting IFN-mediated NF-κB activation and IκBα degradation, also enhanced apoptotic cell death in IFN-treated cells. We conclude that NF-κB activation by IFNα/β is integrated into a signaling pathway through the IFNα/β receptor-1 chain of the type 1 IFN receptor that promotes cell survival in apposition to various apoptotic stimuli.