The major histocompatibility complex (MHC), a region of high gene density, contains a large number of genes relevant to the immune response, belonging to different multigenic families. We studied the genomic organization and polymorphism of a set of genes in the MHC class I region containing the tripartite motif (TRIM), consisting of a RING domain, B-box and coiled coil region, and a B30.2-like domain. A cluster of seven genes at 6p21.33 and two related family members telomeric of the cluster were characterized. All MHC-encoded TRIM-B30.2 genes showed moderate levels of polymorphism, affecting predominantly the RING and B-box domains. In terms of structure, the genes varied by the loss of partial and, in some cases, complete domains. They were strongly conserved in exons 2, 3 and 4, which form the coiled-coil region. The last exon, encoding the B30.2-like domain, is shared with the otherwise unrelated butyrophilin-like (BTN) genes, located 4.3 Mb telomeric of the TRIM-B30.2 cluster. The data are consistent with multiple, ancient duplications giving rise to a set of related genes.