The discovery of extracellular poxvirus inhibitors of type I interferons in 1995 was made by direct inhibition studies, rather than by sequence homology analysis. In fact, the vaccinia virus (strain Western Reserve) prototype of this family, B18R, is more closely related to members of the Ig superfamily than to the cellular type I interferon receptors, at least in terms of overall similarity scores. Nevertheless, B18R binds and inhibits cellular type I interferons with a relatively broad species-specificity. The protein is expressed both as a secreted and cell surface glycoprotein and plays an important role in the pathogenesis of virus infection. In fact, the safest vaccinia strains used historically for smallpox vaccinations either did not express this gene, or the variant protein expressed by the strain was relatively inefficient in terms of type I interferon inhibition.