Combined central and peripheral demyelination (CCPD) is a rare clinical entity characterized by inflammatory demyelination in both the central and peripheral nervous system. A recently conducted nation-wide survey revealed that clinical features of CCPD are atypical for multiple sclerosis, including an absence of oligoclonal immunoglobulin G bands in most CCPD cases. We found that autoantibody responses of CCPD target the nodes and paranodes of Ranvier in the brain and peripheral nerve tissues. We identified anti-neurofascin antibody in the serum from these CCPD patients. CCPD patients showed a significantly higher positive rate of anti-neurofascin antibody than the other limited form of inflammatory demyelinating diseases. Autoantibody responses targeting neurofascins, which are common proteins to the central and peripheral nervous system may play a pivotal role in combined demyelination in CCPD.