We report clinical, electrophysiological, magnetic resonance imaging, and nerve biopsy findings of 2 patients with definite multiple sclerosis and peripheral demyelinating disease. Although it is not easy to assess the real incidence of peripheral neuropathy in patients with multiple sclerosis, this association seems to be rare. The combination of central and peripheral demyelination may be a fortuitous coincidence, but it appears improbable. Alternatively, these patients may represent a specific subpopulation and common immunopathogenetic mechanisms (such as immunological factors, endothelial alterations, and abnormal expression of adhesion molecules) may underly both central and peripheral myelin involvement. The study of these cases might clarify specific mechanisms of pathogenetic significance in demyelinating diseases.