The organization and sequence of the HLA-DR beta chain genes are compared in the two supertypic groups, DRw52 and DRw53, which together account for more than 80% of HLA-DR alleles. From the structural data, we conclude that these two groups represent distinct lineages which have followed different patterns of evolution. The fine structure of the beta chain locus encoding the DRw53 specificity corresponds most closely to the DR beta II pseudogene in the DRw52 haplotypes. Concomitantly, the DR beta I locus in DRw53 haplotypes is more closely related to both of the two expressed DR beta loci of the DRw52 haplotypes (DR beta I and DR beta III). These two loci are the result of a recent duplication. This leads to the proposal that both expressed DR beta chain genes in the DRw52 haplotypes (DR beta I and DR beta III) are derived from a single precursor locus, while the two loci expressed in the DRw53 haplotypes are derived from distinct ancestral loci. The genes encoding DRw52 and DRw53 are therefore not true alleles of the same original locus. A scheme is proposed that accounts for the evolution of DR specificities within the DRw52 and DRw53 groups of haplotypes. It is evident that the different HLA-DR alleles are not structurally equidistant and that one must take into consideration different degrees of heterozygosity or mismatch among the DR alleles.