The autoimmune liver disease, primary biliary cirrhosis (PBC), is associated with debilitating fatigue in a significant proportion of patients. The pathogenesis of fatigue in PBC is unclear, but preliminary studies suggest it has central mechanisms and may have peripheral manifestations. Studies are beginning to elucidate the biological associates of fatigue in PBC, particularly sleep disturbance and autonomic dysfunction. Comprehensive studies investigating the pathogenesis of fatigue in PBC are urgently needed as are large-scale prospective outcome studies.