Several highly polymorphic sequences are present in the beta block of the MHC, especially HLA-B, HLA-C, PERB11.1 (MICA), and PERB11.2 (MICB). It is now apparent that the polymorphism of PERB11.1 is of the same order as that of HLA-A, -B, and -C and it has been suggested that PERB11 could explain some of the disease associations previously attributed to HLA-B. Phylogenetic analysis of PERB11 alpha-domain sequences demonstrates relationships with HLA-B cross-reactive serogroups. In contrast, the transmembrane polymorphisms do not appear to be associated with either PERB11 or HLA-B. These data indicate that PERB11 and HLA-B have evolved in concert from their common ancestors and that the transmembrane polymorphisms have arisen independently and more recently. MHC disease associations will need to be reviewed in the light of mechanisms such as receptor binding and signaling.