An oligonucleotide probe that distinguishes the HLA-DR4, Dw14 allele from other HLA-DR4-associated class II genes was used to identify a common nucleotide sequence shared between the DR beta 1 locus encoding HLA-DR1 (Dw1), Dw16, and DRw10 haplotypes. The presence of this nucleotide sequence correlated with the ability of these haplotypes to stimulate an alloreactive proliferative T-cell clone (clone 14B) raised against a Dw14+ stimulator cell. Alleles of DR beta 1 that differ by one specific nucleotide variation at codon 71 neither hybridize to the Dw14-specific oligonucleotide nor stimulate clone 14B. These data demonstrate the presence of a shared epitope present on serologically distinct DR alleles that is recognized as a specific allodeterminant by a single T-cell clone.