Background: Combined central and peripheral nervous system demyelination is a rare and poorly described phenomenon. Recently, anti-neurofascin antibodies were reported to be positive in 86% of these patients in a Japanese cohort. Yet, there seems to be a clinical, radiological, and serological heterogeneity among these patients. In this report, our aim is to describe characteristics of our patients with this entity and compare with others in the literature. Methods: We report clinical, electrophysiological, radiological, and laboratory characteristics of five patients with both multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy from our institutional database containing 1890 MS patients. Results: Three patients presented with extensive, active demyelination of both central nervous system and peripheral nervous system with hypertrophic peripheral nerves. Plexuses, trunks, division and cords were involved in the process. Oligoclonal band was negative. Conduction block was not detected. Corticosteroid treatment was not adequate. Others had a slowly progressive clinical course. Serum anti-neurofascin antibody was negative. Review of the literature revealed similar cases with active disease, early-onset hypertrophic peripheral nerves, and central demyelination, in addition to other cases with an insidious course. Conclusions: Patients with combined central and peripheral demyelination form a spectrum. Some patients may have an antibody-mediated syndrome with or without anti-neurofascin antibodies and others seem to represent a coincidence.