P18, a member of the INK4 family of cyclin-dependent kinase inhibitors, is a tumor suppressor protein and plays a key cell survival role in a variety of human cancers. Under pathophysiological conditions, the INK4 group proteins participate in novel biological functions associated with neuronal diseases and oxidative stress. Parkinson's disease (PD) is characterized by loss of dopaminergic neurons, and oxidative stress is important in its pathogenesis. Therefore, we examined the effects of PEP-1-p18 on oxidative stress-induced SH-SY5Y cells and in a PD mouse model. The transduced PEP-1-p18 markedly inhibited 1-methyl-4-phenyl pyridinium-induced SH-SY5Y cell death by inhibiting Bax expression levels and DNA fragmentation. Additionally, PEP-1-p18 prevented dopaminergic neuronal cell death in the substantia nigra of a 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine-induced PD mouse model. These results indicate that PEP-1-p18 may be a useful therapeutic agent against various diseases and is a potential tool for treating PD.