Background: : Major Depressive Disorder (MDD) is a leading cause of mental disability worldwide. Despite many studies, the pathophysiology associated with MDD brain is not very clear. It is reported that cellular stress is related to depressive symptoms. Under stressful conditions, intracellular homeostasis processes can be disrupted, which can induce a process of unfolded protein response (UPR) in the subcellular lumen of endoplasmic reticulum (ER). The purpose of this study is to elucidate whether UPR is active in the depressed brain. Methods: : The dorsolateral prefrontal cortex (dlPFC) was used from 23 non-psychiatric controls and 43 MDD subjects. The expression levels of UPR associated genes (GRP78, GRP94, XBP-1, CHOP, ATF4C, and ATF6C) were measured by qRT-PCR. Results: : The level of mRNA expression in MDD subjects was significantly higher for GRP78 (p = 0.008), GRP94 (p = 0.018), and ATF4C (p = 0.03) compared to non-psychiatric controls. Further analysis suggested that changes in the expression of these genes were specifically higher only in those MDD subjects who died by suicide but not in those who died by causes other than suicide when compared with non-psychiatric controls (GRP78, p = 0.007; GRP94, p = 0.041; ATF4C, p = 0.037). Limitations: : This study was performed only in MDD subjects who had died by suicide. Suicide subjects with other psychiatric illnesses need to be included. Conclusions: : Given that UPR is involved in many physiological processes in the brain, including inflammatory response as well as apoptosis, increased expression of UPR genes indicates that ER stress and mediated UPR may be critical factors in suicidality among depressed patients.