Homozygous lymphoblastoid cell lines representing Dw subtypes of the DR2 serotype were studied for structural polymorphism at DR beta. These subtypes included Dw2, Dw12, and non-Dw2/non-Dw12. Analysis by two-dimensional gel electrophoresis showed that two DR beta genes were expressed in each cell line studied. One of these expressed genes encoded a protein that was nonpolymorphic on two-dimensional gel electrophoresis among all subtypes. The second expressed DR beta gene was polymorphic and migrated to a position on two-dimensional gels dependent on the subtype of the cell line. cDNA sequence analysis of the DR beta genes revealed a DR beta gene identical between the Dw2 and Dw12 subtypes, which correlates with the nonpolymorphic spot on two-dimensional gels. A second gene was sequenced that exhibited variability between the Dw2 and Dw12 subtypes. This variability takes the form of clustered point mutations in the first domain of the molecules. The alleles from the DR beta genes of a non-Dw2/non-Dw12 cell line, AZH, were unusual in sequence. In contrast to other DR beta alleles, the AZH genes may have been generated by a double recombinational event between two DR beta loci from a DR2 parent. The DR2 serotype may also constitute a supertypic "family," with one DR beta gene relatively nonpolymorphic, and one that varies with Dw subtype.