The present study deals with the effects of two lipidosis-inducing drugs (chlorphentermine and perhexiline) upon the ultrastructure of large nerve trunks (sciatic and plantar nerves) of adult rats. Subchronic oral administration of high doses of either drug led to comparatively mild lipidosis-like alterations in Schwann cells and in other cell types of both nerve trunks. In addition, plantar nerves, and more rarely sciatic nerves, showed some unspecific lesions such as myelin whorls and ovoids within the outer Schwann cell cytoplasm, intra-axonal accumulations of polymorphous material, and single degenerating fibres. The pathogenetic mechanisms responsible for the non-specific lesions remain to be elucidated. Chlorphentermine was, in all respects, more potent than perhexiline. In general, the drug-induced lesions developing in the fibres of large nerve trunks were less dramatic when compared a) with the severe lipidosis known to occur in neuronal perikarya, and b) with the severe alterations known to develop in preterminal or terminal axon portions of rats kept under similar experimental conditions.