The stress of the endoplasmic reticulum (ER stress) emerges as a new adaptive system determining the fate of cells to survive or die, and may thereby be implicated in the erosion or rupture of atherosclerotic plaques. ER-resident chaperones, among them the 150 kDa oxygen-regulated protein (ORP150), prevents ischemia- and oxidant-induced cell death. Among the various stress-inducing agents present in atherosclerotic lesions, oxidized LDL (oxLDL) triggers apoptotic events that may alter the fragile balance between survival and death of vascular cells during atherosclerosis progression. The aim of this work was to investigate whether and how ORP150 prevent apoptosis induced by oxLDLs in vascular cells. OxLDLs induced ORP150 expression in the ER of human microvascular endothelial cell line (HMEC-1). ORP150 expression was blocked by antioxidants, by the permeant calcium chelator BAPTA-AM, and by xestospongin C, a specific inhibitor of the inositol-1,4,5 trisphosphate (IP3) receptors. ORP150 silencing by siRNA-enhanced oxLDL-induced apoptosis, while forced ORP150 expression increased the resistance of cells via an inhibition of the oxLDL-induced cytosolic calcium deregulation, and the subsequent apoptotic cascade (calpain and caspase activation, cytochrome c release, and apoptosis). In addition, ORP150 inhibited the induction of ER stress by oxLDL, and subsequent ER stress-dependent apoptosis. Altogether, these data indicate that ORP150 inhibits oxLDL-induced apoptosis by 1/ blocking calcium signaling and subsequent apoptosis, 2/ inhibiting ER stress and UPR induction by oxLDL. ORP150 is expressed in advanced atherosclerotic lesions, where it may locally participate to reduce the apoptotic effect of oxLDLs and the risk of plaque rupture.