The heterogeneity within multisystem autoimmune disease was evaluated according to the presence of antinuclear antibodies to ribonucleoproteins and the HLA-A1, B8, DR3 phenotype. Patients with various multisystem autoimmune diseases were tested by a highly sensitive radioimmunoassay for autoantibodies to the small nuclear ribonucleoproteins known as SS-B (La) and ribonucleoprotein (RNP), and HLA phenotypes were determined. The 210 patients included 64 with systemic lupus erythematosus (SLE), 11 with "atypical SLE", 41 with Sjögren's syndrome, 22 with mixed connective tissue disease (MCTD), 21 with rheumatoid arthritis (RA), 16 with primary biliary cirrhosis (PBC) and 35 with autoimmune chronic active hepatitis (A-CAH). Anti-SS-B (La) was present in high frequency in Sjögren's syndrome and was strongly associated with HLA-A1, B8, DR3. Anti-RNP was detected predominantly in MCTD and had no association with HLA-A1, B8, DR3. There were sharply defined serological and genetic differences between primary Sjögren's syndrome and Sjögren's syndrome associated with RA. Anti-SS-B (La) was present in 70% of patients with primary Sjögren's syndrome but in none with Sjögren's syndrome with RA, and the respective frequencies of HLA-A1, B8, and DR3 were 88%, 94% and 75% in the former compared with 38%, 29% and 14% in the latter. Thus primary Sjögren's syndrome differs immunogenetically from Sjögren's syndrome with RA. There was a notable absence of anti-SS-B (La) in PBC, an autoimmune disease associated with the Sjögren's syndrome. These findings illustrate the value of studying immunological and genetic markers in detecting heterogeneity within groups of diseases whose symptoms cannot be distinguished clinically.