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Objective: To explore the mechanism of endoplasmic reticulum stress (ERS) response and related apoptosis in dopaminergic neurons death. Methods: Nerve growth factor (NGF)-treatedPC12 cells were treated with 6-OHDA, MPP+ and rotenone. MTr assay and flow cytometry were used to measure the cell viability and the rate of celluar apoptosis induced by those neurotoxins. The expression of ERS-related gene XBP1, Grp78, CHOP, caspase-12 in drug-treated group and reserpine preincubation group was determined with RT-polymerase chain reaction (RT-PCR) and immunohistochemistry. Results: After the exposure to different toxins, the viability of PC12 cells were decreased by 52%, 44%, 40% at 100μM6-OHDA, 75 μM MPP+, 20 nM rotenone for 24 h respectively. FCM assay confirmed time-dependent cell apoptosis (P ＜ 0.01 ). The gene and protein expression of XBP1, Grp78 in drug-treated group were significantly increased and reached their peaks 8 h after the treatment(P ＜ 0.05).The expression levels of CHOP and caspase-12 gene were increased 16-24 h after the treatment(P ＜ 0.01 ), but the expression level of caspase-12 was inhibited by reserpine preincubayion (P ＜ 0.05). Conclusion: The excessive ERS and relative activated cell apoptosis pathway may be associated with selective death of dopaminergic neurons.