We have isolated and sequenced cDNA clones corresponding to the polymorphic alpha and beta chains encoded by the DR and DQ subregions of two HLA-DR4 haplotypes, LD"KT2" and LD"TAS". These two haplotypes are distinguished on the basis of mixed lymphocyte culture typing. The data indicate that the designation of LD"TAS" as a distinct subtype from Dw13 is very likely due to amino acid differences in the DQ beta chain. In contrast, LD"KT2" differs from TAS and Dw13 by a single amino acid substitution at position 37 of the DR beta 1 chain. The functional and evolutionary significance of these polymorphisms is discussed.