Human herpesvirus 8 (HHV-8, also called Kaposi's sarcoma-associated herpes virus) has been linked to Kaposi's sarcoma and primary effusion lymphoma. HHV-8-encoded viral Fas-associated death domain-like IL-1-converting enzyme inhibitory protein (vFLIP) is one of the few viral proteins to be expressed in latently infected cells and plays a key role in the survival and proliferation of primary effusion lymphoma cells. Two main functions have been ascribed to HHV-8 vFLIP, inhibition of caspase 8/Fas-associated death domain-like IL-1-converting enzyme and activation of NF-κB. In this article, we demonstrate that vFLIP-expressing transgenic mice lack any of the features seen in mice deficient in caspase 8 or Fas-associated death domain protein and are not resistant to Fas-induced apoptosis. On the other hand, these mice display constitutive activation of classical and alternative NF-κB pathways, enhanced response to mitogenic stimuli, and increased incidence of lymphoma. Collectively, our results demonstrate that HHV-8 vFLIP is an oncogenic protein that mimics the signaling activities of caspase 8 during antigen receptor signaling and could contribute to the development of lymphoproliferative disorders via constitutive NF-κB activation independent of inhibition of Fas-induced apoptosis.