Host recognition of intracellular viral RNA and the subsequent induction of antiviral cytokines is tightly regulated at the cellular level, and is a target for manipulation by pathogens and therapeutics alike. As part of a genome-wide screen of cellular proteins required for Hendra virus infection, we identified an uncharacterized protein C6orf106 (C6) required for infection by Hendra virus, in addition to a diverse range of RNA viruses such as highly pathogenic avian influenza virus and West Nile virus. Subsequent work has shown that the previously uncharacterized protein is a negative regulator of the type I interferons, (IFN) α and β and the pro-inflammatory cytokine tumour necrosis factor (TNF) α, in response to the viral RNA mimic poly I:C. We have shown that C6 interacts with IRF3 and reduces levels of transcriptional co-activators p300 and CBP in the nucleus. Type I interferons can play a crucial role in both the innate and adaptive immune responses as well as immunomodulation and inflammation. As such C6 may play a pivotal role in other autoimmune diseases and cancers. In summary we have identified a novel regulator of the type I IFN antiviral host defence immune response, with implications for antiviral immunity against RNA viruses and potential importance in a variety of other diseases.