In order to investigate the HLA component involved in rheumatoid arthritis (RA), we tested genetic models by the marker association-segregation chi 2 (MASC) method, using the HLA genotypic distribution observed in a sample of 97 RA patients. First we tested models assuming the involvement of a susceptibility gene linked to the DR locus. We showed that the present data are compatible with a simple model assuming the effect of a recessive allele of a biallelic locus linked to the DR locus and without any assumption of synergistic effect. Then we considered models assuming the direct involvement of the DR allele products, and we tested the unifying-shared-epitope hypothesis, which has been proposed. Under this hypothesis the DR alleles are assumed to be directly involved in the susceptibility to the disease because of the presence of similar or identical amino acid sequences in position 70-74 of the third hypervariable region of the DRBI molecules, shared by the RA-associated DR alleles DR4Dw4, DR4Dw14, and DR1. This hypothesis was strongly rejected with the present data. In the case of the direct involvement of the DR alleles, hypotheses more complex than the unifying-shared-epitope hypothesis would have to be considered.