The present study assessed the effect of calmodulin antagonists trifluoperazine and W-7 against the cytotoxicity of MPP⁢ and 6-hydroxydopamine (6-OHDA) in relation to the mitochondrial dysfunction and cell death in PC12 cells. Trifluoperazine (an inhibitor of the mitochondrial permeability transition and calmodulin antagonist) and W-7 (a specific calmodulin antagonist) significantly attenuated the MPP⁢- induced cell viability loss in PC12 cells with a maximum inhibition at 0.5∼1μM; beyond these concentrations the inhibitory effect declined. Both compounds at this concentration range did not cause cell death significantly. In contrast to MPP⁢, the trifluoperazine and W-7 did not depress the cytotoxic effect of 6-OHDA. Addition of trifluoperazine and W-7 inhibited the cytosolic accumulation of cytochrome c and caspase-3 activation in PC12 cells treated with MPP⁢ and attenuated the formation of reactive oxygen species and the depletion of GSH, whereas both compounds did not reduce the effect of 6-OHDA. The results show that trifluoperazine and W-7 may attenuate the cytotoxicity of MPP⁢ by inhibition of the mitochondrial permeability transition and calmodulin. Meanwhile, the cytotoxic effect of 6-OHDA seems to be mediated by the actions, which are different from MPP⁢..pdf