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Background: We have shown previously that low density lipoprotein (LDL) can be oxidized in the lysosomes of macrophages, that this oxidation can be inhibited by cysteamine, an antioxidant which accumulates in lysosomes, and that this drug decreases atherosclerosis in LDL receptor-deficient mice fed a high-fat diet. We have now carried out a regression study with cysteamine, which is of more relevance to the treatment of human disease.\ud Methods and Results: LDL receptor-deficient mice were fed a high fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle analysed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32 and 56% compared to the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesions stability, decreased ceroid, and greatly decreased oxidised phospholipids in the lesions. The liver lipid levels and expression of CD68, ACAT2, CYP27 and pro-inflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, HDL cholesterol or triacylglycerol concentrations due to cysteamine. \ud Conclusions: Inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.