Nucleic acid sequences of the second domain encoding exons and the signal sequence encoding exons are presented for a number of HLA-DR beta-chain alleles. There is less polymorphism in these regions than is found in the first domain encoding exon, a result expected from previous amino acid sequence data. The distribution of the polymorphisms follows a locus and supertype pattern. This permits an easy assignment of gene relatedness that is useful for ordering the events which have taken place in the first domain. The relative nonpolymorphism of the second domains within evolutionarily related haplotypes makes them likely candidates for encoding the epitopes recognized by public serologic reagents.