The proprotein convertase subtilisin/kexin type‐9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low‐density lipoprotein receptor (LDLR). As such, loss‐of‐function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase hepatic LDLR levels and lower the risk of developing CVD. The retention of misfolded protein in the ER can cause ER stress and activate the unfolded protein response (UPR); in this study, we investigated whether a variety of LOF PCSK9 variants that are retained in the ER can cause ER stress and hepatic cytotoxicity. Although overexpression of these PCSK9 variants caused an accumulation in the ER of hepatocytes, UPR activation or apoptosis were not observed. Further, ER‐retention of endogenous PCSK9 via splice‐switching also failed to induce the UPR. Consistent with these in vitro studies, overexpression of PCSK9 in the livers of mice had no impact on UPR activation. To elucidate the cellular mechanism to explain these surprising findings, we observed that the 94‐kDa glucose regulated protein (GRP94) sequesters PCSK9 away from the 78‐kDa glucose regulated protein (GRP78), the major activator of the UPR. As a result, GRP94 knockdown increased the stability of GRP78‐PCSK9 complex and resulted in UPR activation following overexpression of ER‐retained PCSK9 variants relative to wild‐type secreted controls. Given that overexpression of these LOF PCSK9 variants does not cause UPR activation under normal homeostatic conditions, therapeutic strategies aimed at blocking the autocatalytic cleavage of PCSK9 in the ER represent a viable strategy for reducing circulating PCSK9. Support or Funding Information This work was supported in part by research grants to Richard C. Austin from the Heart and Stroke Foundation of Ontario (T‐6146), the Heart and Stroke Foundation of Canada (G‐13‐0003064 and G‐15‐0009389), the Canadian Institute of Health Research (74477) Unfolded protein response sensor GRP78 detects misfolded protein in the ER, such as ER‐retained vasopressin mutant VPG17V, dissociates from UPR transducers ATF6, IRE1α and PERK thereby leading to UPR activation. In contrast, Misfolded PCSK9 mutants, such as PCSK9Q152H, are masked from GRP78 by ER‐resident chaperone GRP94. This study highlights a novel mechanism by which certain misfolded proteins, arising from heritable mutations, fail to cause ER stress and UPR activation. Unfolded protein response sensor GRP78 detects misfolded protein in the ER, such as ER‐retained vasopressin mutant VPG17V, dissociates from UPR transducers ATF6, IRE1α and PERK thereby leading to UPR activation. In contrast, Misfolded PCSK9 mutants, such as PCSK9Q152H, are masked from GRP78 by ER‐resident chaperone GRP94. This study highlights a novel mechanism by which certain misfolded proteins, arising from heritable mutations, fail to cause ER stress and UPR activation. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.