Amyotrophic lateral sclerosis (ALS) is a disease of which the underlying etiology and pathogenesis are unknown. Numerous data indicate an important role of the immune system and mitochondrial function in the disease. Primary biliary cirrhosis (PBC) is an autoimmune liver disease resulting from a combination of genetic and environmental risk factors. Patients with PBC develop innate and adaptive immune reactions against mitochondrial antigens. Therefore, common mechanisms could exist in both diseases. We present two cases of ALS with PBC to explore the relationship between the two diseases from the immunological and mitochondrial aspects. Further attention should be given to immune-modulating therapy in ALS patients.