A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins in lysosomes. One of the goals of our research is to identify the chemical etiological factors and understand the molecular mechanisms responsible for the impairment of lysosome function and its impact on macrophage homeostasis. We have discovered that a family of oxidized lipids (cholesteryl hemiesters) occurs at higher concentrations in the plasma of two cohorts of cardiovascular disease patients than in the control cohort. Macrophages exposed to the most prevalent lipid of this family causes lysosome enlargement, peripheral lysosomal positioning, lysosome dysfunction and lipidosis which are irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences to the pathology. The latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.