An ultrastructural examination of intradermal nerve fibers in Fabry disease revealed signs of lipid accumulation and small unmyelinated nerve fiber degeneration. Many axons were swollen, and their internal organelles were lost. In several damaged axons, dense inclusions, probably lipid, were observed. No lipid inclusions were found in Schwann cells, which may indicate that they utilize different metabolic processes or are impervious to ceramide trihexoside. It is hypothesized that Schwann cells and myelin sheaths act as a metabolic barrier protecting the larger myelinated fibers. Lacking this barrier, the smaller unmyelinated fibers are more susceptible to lipid infiltration. This view may explain the small fiber neuropathy in Fabry disease.