INTRODUCTION: Venous abnormalities have been associated with different neurological conditions, and the presence of a vascular involvement in multiple sclerosis (MS) has long been anticipated. In view of the recent debate regarding the existence of cerebral venous outflow impairment in MS due to abnormalities of the azygos or internal jugular veins (IJVs), we have studied the morphological and biological features of IJVs in MS patients. METHODS: We examined (a) IJVs specimens from MS patients who underwent surgical reconstruction of the IJV and specimens of the great saphenous vein used for surgical reconstruction, (b) different vein specimens from an MS patient dead of an unrelated cause, and (c) autoptical and surgical IJV specimens from patients without MS. Collagen deposition was assessed by means of Sirius red staining followed by polarized light examination. The expression of collagen type I and III, cytoskeletal proteins (α-smooth muscle actin and smooth muscle myosin heavy chains), and inflammatory markers (CD3 and CD68) was investigated. RESULTS: The extracranial veins of MS patients showed focal thickenings of the wall characterized by a prevailing yellow-green birefringence (corresponding to thin, loosely packed collagen fibers) correlated to a higher expression of type III collagen. No differences in cytoskeletal protein and inflammatory marker expression were observed. DISCUSSION: The IJVs of MS patients presenting a focal thickening of the vein wall are characterized by the prevalence of loosely packed type III collagen fibers in the adventitia. Further studies are required to determine whether the observed venous alterations play a role in MS pathogenesis.