The relationships of HLA-DR and the newer DS (second D locus) B cell alloantigens (MB and MT) to the clinical and serologic expression of primary and secondary forms of Sjögren's syndrome (SS) were examined in 102 patients (86 whites and 16 blacks). Although HLA-DR3 was significantly increased in whites (25 of 50, 50%) and blacks (4 of 5, 80%) with primary SS compared with race-matched normal controls, it was not appreciably elevated in those with systemic lupus erythematosus (SLE)-SS, rheumatoid arthritis (RA)-SS, or connective tissue disease-SS. The MT2 specificity, however, was more strongly associated with primary SS (86% of whites and 100% of blacks) and also with SLE-SS and RA-SS compared with race-matched normal controls. Furthermore, MT2 was significantly increased in SLE-SS and RA-SS when compared with non-sicca SLE and RA controls. Although primary and secondary SS were most strongly associated with this DS specificity (MT2), the anti-Ro (SS-A) and anti-La (SS-B) antibody responses were more closely allied to DR antigens. HLA-DR3 was increased in anti-Ro positive patients, both whites and blacks, with primary SS (74%) and in total anti-Ro positive subjects (54%) compared with their anti-Ro negative counterparts (38% and 31%, respectively). Among DR3 negative patients, HLA-DR2 correlated with anti-Ro in both primary SS (83%) and in the total SS group (58%). Thus, 96% of Ro antibody positive patients with primary SS had DR3 and/or DR2, as did 80% of anti-Ro positive subjects in all categories.(ABSTRACT TRUNCATED AT 250 WORDS)