In an attempt to define the role of HLA class II genes in predisposition to primary Sjögren's syndrome, patients of two different ethnic groups (Israeli Jews and Greeks of non-Jewish origin) suffering from this disorder were studied. Oligonucleotide genotyping revealed the majority in both groups to carry either DRB1*1101 or DRB1*1104, alleles that are in linkage disequilibrium with DQB1*0301 and DQA1*0501. The high frequency of the two alleles in these SS patients is in contrast with the accepted association of primary SS with HLA-DR3 in Italian and American individuals. Molecular analysis of DQB1 and DQA1 alleles found in American Caucasian and American black SS (or SLE) patients demonstrated high frequencies of DQB1*0201 and DQA1*0501. The fact that the majority of SS patients, across racial and ethnic boundaries, carry a common allele, DQA1*0501, implies its involvement in the predisposition to primary SS. Based on sequence analysis and the computer imaging of the HLA class II molecule structure, a hypothetical model for the role of the DQ molecule in promoting primary SS is proposed.