The possible pathological role of antibody subsets specific for different regions of 60-KD and 52-KD Ro/SSA proteins (Ro60 and Ro52) and La protein is unclear. Previously, we have shown that in patients with Sjögren's syndrome, the fine specificity of Ro60 and Ro52 antibodies, as characterized with synthetic peptides, varied considerably according to the origin of sera. We therefore looked for possible associations of HLA class I and class II alleles with Ro and La IgG antibodies in patients with primary Sjögren's syndrome (n = 24) and secondary Sjögren's syndrome associated with systemic lupus erythematosus (n = 25). Ro60 and Ro52 antibodies were tested by ELISA with the complete parent proteins and with 10 to 24 residue-long peptides of these proteins. Anti-Ro60 antibodies were more frequent in DR3-positive patients and in DQ1-negative patients whereas the presence of Ro52 and La IgG antibodies was significantly increased in patients with A1/B8/DR3 haplotype. Certain HLA associations observed with antibodies reacting with the whole Ro52 protein were not found with antibodies reacting with certain Ro60 and Ro52 peptides and, reciprocally, certain anti-peptide antibodies were linked to particular haplotypes whereas antibodies to the respective parent proteins were not linked to these haplotypes. Thus the production of antibody subsets reacting with different parts or presentations of Ro proteins is, at least in part, influenced immunologically by different HLA haplotypes, and this predisposition may play a role in the pathological development of the disease.