Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs), and the aberrant expressions of MMPs are strongly associated with neuroinflammation and neuronal cell death. In the present study, we found that two well-known dopaminergic neurotoxins, MPP⁺ and 6-OHDA, reduced TIMP-2 expression at the mRNA and protein levels in two human neuroblastoma cell lines (SK-N-BE(2)C and SH-SY5Y). To investigate the role of TIMP-2, these cells were transfected with TIMP-2 expression plasmid and viabilities were compared after treating cells with MPP⁺ or 6-OHDA. It was found that TIMP-2 overexpression attenuated the cell deaths induced by MPP⁺ or 6-OHDA, and that the degree of protection conferred was greater for MPP⁺-treated cells. Furthermore, the introduction of TIMP-2 siRNA into SK-N-BE(2)C cells aggravated the cell deaths induced by MPP⁺ or 6-OHDA. These findings collectively show that endogenously expressed TIMP-2 has a neuroprotective role, and they imply that the inhibition of TIMP-2 expression by MPP⁺ or 6-OHDA may contribute, in part, to neuronal cell death. These findings suggest that TIMP-2 expressional enhancement provides a potential therapeutic strategy for the treatment of neurodegenerative diseases such as Parkinson's disease.