Of 125 patients fulfilling preestablished criteria for severe chronic active liver disease (CALD) and enrolled in a prospective trial of treatment, 15 (12%) presented with morphological features of liver biopsy consistent with the diagnosis of both CALD and primary biliary cirrhosis (PBC) syndrome. Customary clinical, biochemical, and immunoserological studies failed to distinguish fully between these conditions. By contrast, early response to treatment with prednisone and/or azathioprine identified two different groups of patients. Five patients failed to respond, whereas 10 improved and this was followed by resolution of all clinical, biochemical, and morphological evidence of disease activity. Analysis of the initial chemical findings and cumulative bile duct counts from multiple biopsies correlated failure to respond with biochemical and morphological features more consistent with PBC than CALD. Responses to treatment can therefore be utilized when indicated for differentiating CALD with cholangitic features from PBC.