Interleukin-10 Receptor alpha (IL-10Rα) is a transmembrane glycoprotein member of the class II cytokine receptor family. Mature human IL-10 Rα consists of a 214 amino acid (aa) extracellular domain (ECD), a 21 aa transmembrane segment, and a 322 aa cytoplasmic domain. Within the ECD, human IL-10 Rα shares 59% aa sequence identity with mouse and rat IL-10Rα. IL-10 Rα is required for mediating the effects of IL-10,a critical molecule in the control of microbial infections, allergic and autoimmune inflammation, and cancer. IL-10Rα is the ligand specific subunit of the IL-10 receptor complex. Noncovalent dimers of IL-10 bind to IL-10 Rα, resulting in the recruitment of IL-10 Rβ. Immunosuppressive signal transduction through the IL-10 receptor complex can be inhibited by activation of TLR2, 4, or 9, enabling strengthened immune responses during infection. Polymorphisms of human IL-10 Rα may limit viral immune evasion by retaining full responsiveness to human IL-10 but responding weakly to the cytomegalovirus homolog of IL10.