Several lines of evidence support that methamphetamine (METH) toxicity plays a pivotal role in neurodegenerative diseases. However, the molecular mechanisms underlying METH-induced neurotoxicity are still unclear. In addition, Ras modulated death signaling has been continually reported in several cell types. In this study, intracellular Ras-dependent death signaling cascade activation was proposed to contribute to METH-induced neuronal cell degeneration in dopaminergic SH-SY5Y cultured cells. Exposure to a toxic dose of METH significantly decreased cell viability, and tyrosine hydroxylase phosphorylation, but increased c-Jun phosphorylation and active, GTP-bound Ras in cultured SH-SY5Y cells. Farnesyltransferase inhibitor, FTI-277, an inhibitor of the enzyme catalyzed the farnesylation of Ras proteins was able to diminish the toxic effects of METH on induction in cell degeneration, activation in c-Jun-N-terminal kinase cascades, and Ras activation in SH-SY5Y cells. The results of this study show that activation in Ras signaling cascade may be implicated in the METH-induced death signaling pathway in neuroblastoma SH-SY5Y cells.