Interferons (IFN) are a family of cytokines with potent antiviral, antiproliferative and immunomodulatory properties, classified based on their binding specificity to cell surface receptors. There are more than a dozen closely related IFN alpha subtypes found in both the human and mouse genome, each sharing about 80% amino acid (aa) sequence homology. There are several variants of human IFNA2, IFNA2a, IFNA2b and IFNA2c, which only differ by a few point mutations. The extracellular domain (ECD) of mature human IFNA2b shares 59% aa sequence identity with mouse IFNA2. The type I IFNs bind to the interferon alpha receptor (IFNAR), which consists of two subunits: IFNAR1 (alpha -subunit) and IFNAR2 (beta -subunit). While individual IFN alpha subtypes are known to display unique efficacies to viral protection, nothing is known about functions unique to IFNA2 in human physiology. However, IFNA2 has become the representative type I IFN subtype used in basic research and numerous clinical applications. Since being first approved for treatment of hairy cell leukemia in 1986, IFNA2b has been approved for the treatment of several malignancies including AIDS-related Kaposi’s sarcoma, malignant melanoma and chronic hepatitis B and C. More recently, human IFNA2b has been tested as a potential treatment for COVID-19.