Classical swine fever is a notifiable disease of pigs. The causative agent, classical swine fever virus (CSFV), is highly contagious and causes mild to severe haemorrhagic disease depending on the virulence of the strain. The RNA genome of CSFV is translated as a single polyprotein that is processed to yield 12 proteins. Like other pestiviruses, the first protein to be translated is the N-terminal autoprotease termed N(pro). A novel pestiviral protein with no known cellular homologues, N(pro) antagonizes type I interferon (IFN) induction by binding and targeting the transcription factor IFN regulatory factor 3 (IRF-3) for ubiquitin-dependent proteasomal degradation. In this study, CSFV-infected PK-15 cells and stable cell lines were used to show that N(pro) is itself an unstable protein that is targeted for proteasomal degradation in a ubiquitin-dependent manner. In addition, N(pro) is not degraded as a direct consequence of its ability to interact with IRF-3 or to target IRF-3 for proteasomal degradation.