Vaccinia virus (VV) and other orthopoxviruses express a soluble type I interferon (IFN) receptor that for VV strain Western Reserve is encoded by gene B18R. The 60-65 kDa glycoprotein is related to the interleukin-1 receptors and is a member of the immunoglobulin superfamily, unlike other type I IFN receptors, which belong to the class II cytokine receptor family. The receptor has high affinity (KD, 174 pM) for human IFN alpha and, unlike other type I IFN receptors, has broad species specificity, binding to human, rabbit, bovine, rat, and mouse type I IFNs. This may have aided VV replication in multiple host species during evolution. A VV B18R deletion mutant is attenuated in a murine intranasal model. This type I IFN receptor represents the fourth VV protein that interferes with IFN and the fourth soluble cytokine receptor expressed by poxviruses.