Iron-saturated transferrin is a ubiquitous growth factor that plays a critical role in cellular iron uptake, growth and proliferation. Here we have studied the expression and distribution of transferrin receptors and iron uptake following injury of the rat sciatic nerve. Axotomy led to a massive but transient increase (days 2 - 9, maximum day 4) in [125I]transferrin binding at the site of the injury and in the distal, denervated part of the crushed or resected sciatic nerve, shortly preceding the time course of cellular proliferation (Friede and Johnstone, Acta Neuropathol, 7, 218 - 231, 1967; Jurecka et al., Acta Neuropathol, 32, 299 - 312, 1975). An additional, transient increase in specific binding was observed during reinnervation after reconnection of the resected sciatic nerve. Immunocytochemistry using the Ox-26 monoclonal antibody revealed strong and simultaneous expression of the transferrin receptor protein on two different cell types: on a subpopulation of blood-borne macrophages invading the injured peripheral nerve and on Schwann cells reacting to denervation and reinnervation. In addition, studies using intravenously injected radioactive iron (59Fe3+) showed a massive increase in endoneural iron uptake confined to the lesion site and to the distal part of the axotomised sciatic nerve, parallel to the time course of reactive transferrin receptor expression. Since iron is an essential cofactor of a number of key enzymes needed in energy metabolism and DNA synthesis, these data suggest that the induction of transferrin receptor expression may play an important role in the regulation of cellular growth and proliferation during peripheral nerve regeneration.