The periaxonal space of peripheral myelinated axons was studied in the mutant Syrian hamster with hindleg paralysis, an experimental model of neuropathy. Despite pronounced alterations of the axon and the surrounding sheath, sometimes leading to demyelination, the periaxonal space showed remarkable resistance to change in most instances. When the space was widened as the result of the infiltration of extracellular fluid, the axon was found at the periphery of the enlarged inner perimeter of the sheath. Even under these extreme conditions the axon maintained close to normal distance from the inner collar of cytoplasm. The significance of these findings with regard to both the normal anatomical relationship within the sheath and to the mechanisms of demyelination are discussed.