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HLA class II genes have been implicated in susceptibility to a number of diseases. We have previously identified two allelic variants of DQw3 and have shown that DR4-DQβ3.2 haplotypes are associated with increased risk of IDDM whereas DR4-DQβ3.1 haplotypes are not. DR5 and DR8 DQw3 + individuals are exclusively DQβ3.1 and share numerous restriction sites within the DQβ genes with DR4-DQβ3.1 individuals. In order to compare the DQβ3.1 genes associated with different haplotypes, we have sequenced coding and noncoding regions of the DQβ genes from a DR4-DQβ3.1 HTC (ER) and a DR8-DQβ3.1 HTC (LUY). LUY and ER DQβ genes share nucleotide substitutions in both the β1 and β2 exons, yielding six amino acid replacements distinguishing them from DQβ3.2. In the noncoding regions as well, LUY and ER share nucleotide substitutions distinguishing their DQβ3.1 genes from DQβ3.2. These data support the concept that the DQβ3.1 allele was introduced onto different backgrounds via homologous recombination.