We propose that chronically denervated Schwann cells may be less able to respond to axonal signals than their acutely denervated counterparts, and that this lack of sensitivity may be one reason why axons fail to regenerate into chronically denervated nerve stumps. To test this proposal we have used in situ hybridization, and quantitative and qualitative immunohistochemistry to compare the expression of c-erbB2 and c-erbB4 receptors in Schwann cells denervated for up to 6 months in vivo, with that seen in Schwann cells denervated for similar periods of time but then exposed to regenerating axons. The results were correlated with the extent of axonal regeneration in each experimental group as assessed from transverse sections which had been double-immunolabelled using anti S-100 and anti-beta tubulin III antibodies. Since c-erbBs are receptors for neuronally derived neuregulins we probed the appropriate axotomised DRG neurons for expression of GGF2 mRNA. When the denervated distal stumps were anastomosed to acutely transected proximal stumps, GGF expression in DRGs increased transiently during the first week: we assume that secreted GGF2 derived from regrowing axon sprouts would have been available to Schwann cells in all distal stumps. Endoneurial cell proliferation (predominantly Schwann cell proliferation); levels of expression of c-erbB receptors by Schwann cells, and the degree to which axons regenerated into the distal stumps all decreased as the period of prior denervation increased: the longer the time of denervation, the lower the expression of c-erbBs in Schwann cells, and the smaller the percentage of bands of Bungner which were re-innervated.