Chronic inorganic manganese (Mn) exposure has been known to induce neurological disorders similar to Parkinson's disease (PD). Apoptosis has been shown to be involved in manganese-induced neurotoxicity. However, the up-stream molecular mechanisms for cell apoptosis are not established. α-Synuclein (α-syn) is a major component of intracellular inclusions in PD, Alzheimer's disease (AD), and other neurodegenerative disorders. We investigated the role of α-syn in manganese chloride (MnCl2)-induced apoptosis. Results show that MnCl2 enhanced transcriptional and translational α-syn overexpression, and apoptosis as measured by caspase-3 activity and flow cytometry. Overexpressing α-syn exacerbated manganese-induced apoptosis, whereas antisense α-syn treatment significantly reversed MnCl2-induced apoptosis in human neuroblastoma SH-SY5Y cells. In conclusion, our results imply that intracellular α-syn overexpression may be responsible for MnCl2-induced apoptosis.