Ciliary neurotrophic factor (CNTF), a multipoietic factor, on a variety of neurons, prevents axotomy-induced motoneuron loss and can improve the outcome of murine motor neuron disease (MND). We carried out a study to determine whether other cytokines rescue spinal motoneurons from axotomy-induced cell death. Unilateral sciatic nerve was transected in neonatal rats. Two doses of recombinant murine cholinergic differentiation factor/leukemia inhibitory factor (CDF/LIF), recombinant rat CNTF, recombinant human granulocyte-colony stimulating factor (G-CSF), recombinant human interleukin-6 (IL-6), recombinant human tumor necrosis factor beta (TNF beta), or vehicle were administered daily for 2 weeks by intraperitoneal injection. After treatment, the number of spinal motoneurons was determined at the level of L4-5 segments. In comparison with vehicle, the higher doses of CDF/LIF, CNTF, and IL-6, and the lower doses of CDF/LIF and IL-6 significantly retarded the loss of motoneurons. G-CSF and TNF beta failed to inhibit motoneuron death. CDF/LIF and IL-6 rescued motoneurons from the retrograde death following axotomy, in a similar manner to CNTF. These results provide evidence that several cytokines may have therapeutic potential in human axonopathy or MND.