Auto-antibodies are an integral part of the diagnostic armentarium in chronic cholestatic liver disorders, such as primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC),auto-immune cholangitis, or overlap syndromes among these disorders. However, care should be taken not to overestimate the diagnostic specificity. Auto-antibodies to mitochondrial antigens(AMAs) with reactivity to the E2 subunit of the pyruvate dehydrogenase complex represent the hallmark antibody for the diagnosis of PBC, whereas antinuclear antibodies (ANAs)with low disease specificity are found in up to 50% of these sera. Antibodies that recognize nuclear envelope proteins exert a similarly high diagnostic specificity as AMA in PBC but occur at a rather low prevalence. The role of auto-antibodies is less well-studied for patients with PSC, but there is growing evidence that only antineutrophil cytoplasmic antibodies(ANCAs) are of relevant diagnostic significance. In contrast, auto-antibodies-particularlyAMAs-do not contribute to the diagnosis of auto-immune cholangitis, whereas ANCAs,ANAs, smooth muscle antibodies, and AMAs are of varying significance in PBC-auto-immune hepatitis (AIH) or PSC-AIH overlap syndromes. It has been widely accepted that the course of the auto-antibody serum end point titers are not suited for the clinical management of patients with chronic cholestatic liver disorders. Additionally, auto-antibodies in these disorders usually do not contribute to the immunopathogenesis of the disease.