A recently developed Farr-type radioimmunoassay for the detection of antibodies to tritium-labeled HeLa cell cytoplasmic ribosomes was evaluated as a serologic test in a variety of liver diseases. Ribosomal antibodies were detected in the sera of 31.4% of 70 patients with chronic active hepatitis (CAH) and primary biliary cirrhosis compared with only 4.2% of patients with chronic persistent hepatitis, acute viral hepatitis, alcoholic liver disease, and miscellaneous liver diseases (X2 = 17.89, P less than 0.001). The level of ribosomal binding activity was also significantly higher in sera of patients with CAH and primary biliary cirrhosis (15.4% vs 6.5%; t = 5.61, P less than 0.001). The antibodies were observed almost exclusively in HBsAg-negative CAH with autoimmune features and infrequently at lower titer in HBsAg-positive CAH or CAH without HBsAg or autoantibodies. Inhibition experiments with purified ribosomal RNA suggested that the ribosomal antibodies are in part reactive with ribosomal RNA. Ribosomal antibodies appear to represent another example of the exaggerated immune response associated with CAH and primary biliary cirrhosis.