The inherently low regenerative capacity of the CNS demands effective strategies to inhibit neurodegeneration in acute lesions but also in slowly progressive neurological disorders. Therefore, therapeutic targets that can interact with the degeneration cascade to block, not just postpone, neuronal degeneration need to be defined. Bcl-X(L), a protein protecting the integrity of the mitochondrial membrane potential, was investigated for its neuroprotective properties in a long-term in vivo model of neuronal cell death. An AAV-2-based vector was used to express both Bcl-X(L) and EGFP in retinal ganglion cells (RGCs) of the adult rat retina. Transection of the optic nerve results in degeneration of RGCs in control retinae, while Bcl-X(L)-overexpressing ganglion cells were protected from degeneration. At 2 weeks after axotomy, 94% of the transduced RGCs survived the lesion (15% in controls). For the first time, we investigated RGC survival up to 8 weeks after axotomy and detected that 46% of the Bcl-X(L)-overexpressing RGCs still survived, representing significantly increased neuroprotection compared to neurotrophin-based approaches. We could also show that the axons of AAV-Bcl-X(L)-transduced RGCs remained morphologically intact after the lesion, thus providing the basis for regeneration-inducing attempts.