Reduced oxygen availability promotes triglyceride accumulation in hearts (1) and cardiomyocytes (2). Although it is well established that lipid accumulation in hypoxic conditions can be at least partly explained by a metabolic shift from oxidation of glucose and fatty acids to glycolysis (3, 4), it is not clear whether these metabolic changes alone are sufficient or if there is also a requirement for increased uptake of lipids. Potential mechanisms for lipid uptake include receptor-mediated endocytosis of lipoproteins, lipoprotein lipase–catalyzed (LPL-catalyzed) hydrolysis of triglycerides (5), and protein-facilitated uptake of fatty acids (reviewed in ref. 6). Accumulation of triglycerides in the myocardium is associated with impaired cardiac function (7–10), but it is not known whether there is a causative link between these 2 phenomena. Intracellular triglycerides, which are stored in the hydrophobic core of lipid droplets and surrounded by amphipathic lipids and proteins (reviewed in ref. 11), are most likely very inert and thus not directly lipotoxic (12). However, it is possible that products formed during the degradation of triglycerides, such as diglycerides and fatty acids, and ceramides, which are formed from fatty acids, may have a pronounced effect on myocardial function and survival. Hypoxia/ischemia is also known to promote ER stress or the unfolded protein response. This response involves the production of chaperones to promote the folding process and maintain ER homeostasis, but unresolved ER stress leads to apoptotic cell death (reviewed in refs. 13, 14). Recent evidence suggests that ER stress plays an important role in the progression of cardiovascular diseases including ischemic heart disease, indicating that strategies to reduce ER stress may be beneficial in the ischemic heart (15). The aims of this investigation were to clarify the mechanisms behind the accumulation of lipids in the myocardium during ischemia and to determine the effect of lipid accumulation on survival following an acute myocardial infarction. We show that hypoxia/ischemia increased expression of the VLDL receptor (VLDLR) in HL-1 cardiomyocytes and mouse hearts, and that expression of the VLDLR was essential for lipid accumulation during hypoxia/ischemia. Furthermore, VLDLR mRNA expression was higher in ischemic versus nonischemic human hearts. Importantly, survival was increased and infarct size, ER stress, and apoptosis were reduced in Vldlr–/– compared with Vldlr+/+ mice following an induced myocardial infarction. We also demonstrated that blockade of the VLDLR with antibodies reduced ischemia-induced lipid accumulation, ER stress, and apoptosis in mouse heart tissue. We therefore propose that the VLDLR-induced lipid accumulation in the ischemic heart worsens survival by increasing ER stress and apoptosis.