The MHC superfamily (MhcSF) consists of immune system MHC class I (MHC-I) proteins, along with proteins with a MHC-I-like structure that are involved in a large variety of biological processes. beta2-Microglobulin (B2M) non-covalent binding to MHC-I proteins is required for their surface expression and function, whereas MHC-I-like proteins interact, or not, with B2M. This study was designed to predict B2M binding (or non-binding) of newly identified MhcSF proteins, in order to decipher their function, understand the molecular recognition mechanisms and identify deleterious mutations. IMGT standardization of MhcSF protein domains provides a unique numbering of the multiple alignment positions, and conditions to develop such predictive tool.