In this study, we investigated whether brain-derived neurotrophic factor (BDNF) and neurotrophin-4/5 (NT-4/5) can achieve prolonged protection on retinal ganglion cells (RGCs) and whether site of axon injury modulates RGC response to neurotrophins. Two optic nerve (ON) injury paradigms, proximal and distal transections, were used. Autologous sciatic nerves were grafted onto ON stump in some animals to provide a suitable environment for axons to regrow. Multiple intravitreal injections of saline, BDNF, or NT-4/5 were performed. Immunohistochemistry was used to determine the proportion of RGCs that were expressing trkB. Twenty days after proximal injury, both BDNF and NT-4/5 promoted RGC survival; this protection diminished 30 days after injury. One month after distal injury, BDNF, but not NT-4/5, promoted RGC survival (by 2-fold). No difference in the proportion of trkB expressing RGCs among the viable ones was seen between the two injury models or after BDNF treatment. Interestingly, the mean size of RGC somata was larger after proximal injury than distal injury. This study demonstrates that (1) RGCs respond differently to neurotrophins under different injury conditions, (2) BDNF but not NT-4/5 significantly enhances survival of distally but not proximally injured RGCs over a prolonged period.