The recent development in the authors' laboratory of a sensitive bead assay able to detect AMA in 20% of otherwise AMA-negative sera seems to support the hypothesis that many AMA-negative cases of primary biliary cirrhosis (PCB) are secondary to limits in the methods used and do not represent an independent clinical entity. Clinical data demonstrate that patients without detectable serum AMA do not differ in their natural history from their seropositive counterparts. Anti-nuclear antibodies have been associated repeatedly with more severe disease and are helpful tools in the management of patients who have PBC, particularly those lacking AMA.