Expression of the transcription factor c-Jun is induced in neurons of the central nervous system (CNS) in response to injury. Mechanical transection of the nigrostriatal pathway at the medial forebrain bundle (MFB) results in the delayed retrograde degeneration of the dopamine neurons in the substantia nigra pars compacta (SNc) and induces protracted expression and phosphorylation of c-Jun. However, the role of c-Jun after axotomy of CNS neurons is unclear. Here, we show that adenovirus-mediated expression of a dominant negative form of c-Jun (Ad.c-JunDN) inhibited axotomy-induced dopamine neuron death and attenuated phosphorylation of c-Jun in nigral neurons. Ad.c-JunDN also delayed the degeneration of dopaminergic nigral axons in the striatum after MFB axotomy. Taken together, these findings suggest that activation of c-Jun mediates the loss of dopamine neurons after axotomy injury.