AbstractB7‐1 and B7‐2 are members of the immunoglobulin superfamily (IgSF) and important regulators of T cell‐mediated immune responses. Despite sharing only limited sequence identity, B7‐1 and B7‐2 bind common receptors, CD28 and CTLA‐4, on T cells and have similar functional properties. We have found that the extracellular V(ariable)‐like domains of B7‐1 and B7‐2 share significant sequence similarities with 3 major histocompatibility complex (MHC)‐encoded members of the IgSF: butyrophilin, myelin/oligodendrocyte glycoprotein, and the chicken MHC molecule, B‐G. This raises the question whether there is an evolutionary link between the MHC, which encodes molecules regulating the antigen specificity of T lymphocyte responses, and B7 molecules, which co‐stimulate these responses in antigen‐nonspecific fashion.