Poxvirus have evolved an array of mechanisms to circumvent the effects of type I interferons (IFNs), a group of cytokines known for their ability to confer resistance to viral infection. For example, the virulent rodent pathogen Ectromelia virus, that causes mousepox, encodes a secreted decoy receptor named EVM166 that is able to bind and inhibit type-I INFs. This entry contains a crystal structure of EVM166 in complex with murine IFNα5 and reveals a striking similarity between EVM166 and the ectodomain of the human receptor for IL-1β. The regions buried by EVM166 on IFNα5 are thought to be crucial for its’ interactions with the host-encoded INF-α receptor (a cell-surface heterodimer consisting of the two chains IFNAR1 and IFNAR2). Many species within the orthopoxvirus genus encode decoy receptors for type-I INFs that have sequence similarity to EVM166. These include Vaccinia, Cowpox, and Variola, among others. Sub-species that lack or encode truncated versions of EVM166 display a significantly attenuated phenotype in mice demonstrating the importance of this decoy receptor as a virulence factor. The information contained in this entry may prove useful in the future development of antiviral therapeutics targeted against poxviruses. It may also prove useful in the design and creation of novel anti-inflammatory therapeutics.