Endoplasmic reticulum (ER) stress has been shown to be associated with the pathogenesis of neurodegenerative disorders including Parkinson's disease (PD). HtrA2/Omi, from its participation in protein quality control, is involved in ER stress. However, little is known about the relationship between HtrA2/Omi and ER stress in PD. Here, we explored the association of HtrA2/Omi and ER stress in a cell model of PD and found that the expression level of HtrA2/Omi decreased with ER stress induction in 6-OHDA-treated SH-SY5Y cells. Furthermore, silencing endogenous expression of HtrA2/Omi with siRNA resulted in aggregated ER stress and cell death. Taken together, our results show that HtrA2/Omi may exert a protective function in 6-OHDA-induced cell death by regulating ER stress-related proteins. This research offers some clues as why mutations in HtrA2/Omi lead to higher susceptibility in some PD patients.