The prevalence of autoimmune associations was determined in 113 patients with primary biliary cirrhosis who participated in a therapeutic trial of D-penicillamine. Eighty-four percent of the patients had at least one associated autoimmune disease and 41% had two or more such diseases in addition to primary biliary cirrhosis. Keratoconjunctivitis sicca, which was present in 66% of the patients, was the most commonly associated autoimmune disease. In most of the patients the autoimmune disease was recognized after the diagnosis of primary biliary cirrhosis had been made. The prevalence of autoantibodies in selected subgroups of patients ranged from 70% (rheumatoid factor) to 22% (anti-native DNA). Polyclonal elevation of serum immunoglobulins was a consistent finding, and frequently all three major isotypes were simultaneously increased. Only IgA elevations correlated with histologic progression of primary biliary cirrhosis. The prominent involvement of epithelial tissues in the autoimmune disease of primary biliary cirrhosis suggests that an autoimmune syndrome affecting the secretory immune system is associated with the pathogenesis of primary biliary cirrhosis and the coexisting autoimmune diseases.