The WldS mouse is a spontaneous mutant that is characterized by the phenotype of delayed degeneration of transected nerves (slow Wallerian degeneration). Molecular genetic analysis identified a mutation in this animal that codes for a unique protein expressed in brain tissue of WldS mice. We asked whether the WldS phenotype, in addition to delaying axonal degeneration after axotomy, might provide neuroprotection against toxic neuropathy. In dorsal root ganglia (DRG) cultures, neurites from WldS transiently exposed to vincristine not only resisted axonal degeneration but resumed growth after withdrawal of the toxin. Neurites from wild type mice died rapidly and did not recover. To prove that the identified mutation and its protein product are responsible for the WldS phenotype, we used an adenoviral gene transfer system to deliver the WldS to rat DRG neurons. Rat neurons expressing the WldS protein were resistant to vincristine-induced axonal degeneration, confirming the functional significance of the identified gene mutation. These data provide evidence that the WldS protein can be neuroprotective against vincristine neuropathy, and possibly other disorders characterized by axonal degeneration. In addition, delivery of this gene to wild type cells can transfer the WldS phenotype, providing the possibility of "gene therapy" for peripheral neuropathy.