Viral infection initiates a cellular innate immune response that ultimately attempts to limit viral replication and prevent escalating infection through expression of host antiviral proteins and mediators of inflammation. Recent work by us and others has highlighted the importance of the host antiviral protein viperin in this process, with its ability to limit the replication of a variety of viruses. In addition to its antiviral activity we have demonstrated that viperin also plays a role in augmentation of both the Jak-Stat pathway and TLR3 signaling. Viperin is able to significantly increase the activity of both ISRE and GAS driven luciferase reporter constructs in the presence of stimuli, as well as increase mRNA expression of specific ISGs. However a viperin mutant unable to localize to membranous structures had no impact on ISRE or GAS activity. Viperin expression also increased STAT-1 phosphorylation at tyrosine 701. Similar experiments using the dsRNA analogue poly I:C to stimulate TLR3 activation demonstrated an increase in NF-kB luciferase driven reporter activity in the presence of viperin that was not noted using the viperin mutant. Clearly viperin is a complex multifunctional protein, that appears to be able to inhibit replication of multiple viruses, however, we also demonstrate for the first time that viperin augments early innate signaling pathways, which may assist in explaining its ability to limit such a broad range of viral pathogens.