The neuropoietic cytokine cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF) acts as a trophic factor, enhancing neuronal survival, and as a differentiation factor, altering neuronal gene expression. There is also evidence that its plays a role in the response of adult neural tissue to injury. We have examined this possibility further in rats by analyzing changes in the levels of mRNAs for CDF/LIF and its two receptor subunits in response to peripheral nerve damage in culture and in vivo. Using a quantitative RNase protection assay, we find that CDF/LIF mRNA increases dramatically (176-fold) in adult, but not neonatal, sympathetic ganglia and in adult dorsal root ganglia and sciatic nerve after organ culture for 24 hr. This mRNA is clearly detectable by in situ hybridization only in the nonneuronal cells of these structures. When the sciatic nerve is transected in vivo, CDF/LIF mRNA increases significantly in the regions immediately proximal and distal to the lesion site. The mRNA for the ligand binding subunit of the CDF/LIF receptor complex decreases somewhat upon culture and nerve section. The dramatic rise in CDF/LIF mRNA after nerve injury is further evidence that this cytokine is involved in the response to damage, a function that overlaps with its postulated role in wounding or infection in several nonneural tissues.