Background: Atherosclerosis is a metabolic disorder characterized by hyperlipidemia and chronic inflammation that is initiated by endothelial dysfunction and altered lipid homeostasis. Sigma1 receptor (Sigmar1) is a ubiquitously expressed chaperone protein known to have a role in lipid metabolism and ER-mitochondrial lipid transport. Although studies showed a correlation between Sigmar1 inhibition and induction of inflammation, the role of Sigmar1 in regulating vascular inflammation during atherosclerosis remained unknown. Hypothesis: Absence of Sigmar1 will accelerate the development and progression of atherosclerosis by inducing endothelial inflammation and mitochondrial dysfunction. Methods and Results: We used a hypercholesterolemia model induced by AAV8-PCSK9 injection followed by 12 weeks of western diet (WD) in wildtype (Wt) and global Sigmar1 knockout (Sigmar1 -/- ) mice to determine the role of Sigmar1 in diet-induced atherosclerosis. We also used human aortic endothelial cells (HAEC) and CRISPR-Cas9 mediated Sigmar1 knockout HAECs (HAEC hKO ) to delineate the molecular mechanisms in vitro . Sigmar1 protein level was notably decreased in the human and mouse atherosclerotic tissues and in HAECs treated with inflammatory trigger, LPS+IFNγ. We observed increased atherosclerotic plaque area in aorta by en face analysis in Sigmar1 -/- mice compared to Wt mice subjected to PCSK9/WD model. LPS+IFNγ treated HAEC hKO showed significant upregulation of EC adhesion molecules (VCAM1, ICAM1) and activated nuclear factor NFκB expressions than the control HAEC hWT . Since mitochondrial dysfunction and elevated reactive oxygen species (ROS) generation play a role in inflammation and diseases, and Sigmar1 is known to regulate mitochondrial function, we wanted to dissect the contribution of EC-Sigmar1 in vascular inflammation. Both lack of Sigmar1 and LPS+IFNγ stimuli significantly reduced mitochondrial respiration in HAEC hKO cells and induced ROS production along with the induction of inflammation. Conclusion: So, lack of Sigmar1 leads to increased atherosclerotic plaque area in mice in response to PCSK9/WD suggesting a novel protective role for Sigmar1 in the development and progression of atherosclerosis and vascular inflammation.