In this study we have shown that BTV expresses a previously uncharacterised non-structural protein that favours viral replication in cells in an antiviral state. By constructing deletion mutants by reverse genetics, we showed that NS4 is dispensable for viral replication in vitro, both in mammalian and insect cells, and in vivo in murine experimental models. However, the coding sequence in the NS4 reading frame of segment 9 is highly conserved in BTV and in related Orbiviruses [29, 50] , suggesting that it must be essential for the maintenance of BTV in nature. Indeed, we have found that NS4 confers a replication advantage to BTV-8 in cells pre-treated with type I IFN.