In neonatal rats, intraocular injections of brain-derived neurotrophic factor (BDNF) or neurotrophin 4/5 (NT-4/5) enhance the survival of retinal ganglion cells (RGCs) following superior colliculus (SC) ablation [Q. Cui, A.R. Harvey, At least two mechanisms are involved in the death of retinal ganglion cells following target ablation in neonatal rats, J. Neurosci., 15, 1995, pp. 8143-8155.]. The aim of the present study was to determine if: (i) fetal tectal tissue grafted into the lesion site, or (ii) neurotrophins applied centrally to the injured SC, also decreased lesion-induced RGC death. Nuclei of tectally projecting RGCs were identified by injecting diamidino yellow (DY) into the left SC of 2-day-old (P2) Wistar rats. Injected SCs were lesioned at P4. In some animals, embryonic (E16) tectal tissue was then implanted into the lesion cavity; host rats were perfused 24 h or 20 days later. In short-term (24-h) studies, the number of DY-labelled pyknotic profiles was compared to the number of normal DY-labelled RGCs in retinal wholemounts (right eyes). The proportion of dying RGCs in animals with grafts (10.7%, n = 17) was not significantly different from lesion-only rats (13.2%, n = 26). Nonetheless, the long-term (20-day) study showed that, in most rats, fetal tectal tissue survived in the lesion cavity and in some cases, the grafts received host retinal input. In another group, different doses of BDNF or NT-4/5 were applied to the SC after P4 tectal lesions. Rats were perfused 24 h later and the number of pyknotic vs. normal DY-labelled RGCs was determined. Initial trials in which SC lesions were filled with gelfoam soaked in BDNF or NT-4/5 were unsuccessful; however, RGC death was reduced (p < 0.05, Dunnett's test) in rats that received gelfoam implants as well as focal neurotrophin injections into SC rostral to the lesion. The lowest pyknotic rate in individual animals from the BDNF and NT-4/5 groups was 2.41% and 2.01%, respectively. Overall, the proportion of dying RGCs was 7.0% (n = 8) for BDNF and 7.4% (n = 17) for NT-4/5 treated rats. Normal RGC densities were also significantly higher in these animals. NT-4/5 topically applied to the posterior surface of the eye did not reduce RGC death. The data show that the viability of injured neonatal RGCs is increased by specific retrograde neurotrophin-mediated survival signals which can be activated from the SC.