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Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-Palmitoyl-2- arachidonoyl-sn-glycero-3-phosphatidylcholine, is a pro-inflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT, and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein endothelial cells with POVPC, simvastatin, or both, and determined their effect on endothelial cell viability, morphology, tube formation, proliferation, and generation of nitric oxide (NO) and superoxide anion (O2●-). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect endothelial cell viability, but altered cellular morphology from cobblestone-like endothelial cells to a spindle-like mesenchymal cell morphology. POVPC increased O2- generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-β), TGF-β receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production, and expression of CD31 and endothelial nitric oxide synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O2●- and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-β/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-β/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.