Background: Peroxisome proliferator-activated receptor-g (PPAR-g) exhibits anti-inflammatory and anti-diabetic properties, and is protective against cardiovascular diseases. This study aimed to determine the effects of a PPAR-g agonist pioglitazone on atherogenesis in an ApoE knockout mouse (ApoE(-/-)) diabetic mouse model and in a cultured vascular smooth muscle cells (VSMCs) model. Material/Methods: Male ApoE(-/-) mice were rendered diabetic by 5 daily intraperitoneal injections of streptozotocin. Pioglitazone (20 mg/kg/d) or PPAR-g inhibitor GW9662 (1 mg/kg/d) were administered for 12 weeks. At the end of treatment, mice were killed and the aortae were isolated. Oil Red O staining was used to evaluate atherosclerotic plaque area. H&E staining was used to evaluate the number of complicated plaques. Western blotting and immunohistochemistry were used to determine the expression of advanced glycation end-products (RAGE) and PPAR-g. The effects of pioglitazone and GW9662 on RAGE and PPAR-g expression were examined in cultured primary mouse VSMCs in hyperglycemic conditions. Results: Administration of pioglitazone in diabetic ApoE(-/-) mice successfully reduced atherosclerotic plaque area and the number of complicated plaques. Moreover, pioglitazone inhibited RAGE and stimulated PPAR-g protein expression in atherosclerotic plaques of diabetic ApoE(-/-) mice. In cultured VSMCs upon high-glucose challenge, pioglitazone downregulated RAGE mRNA and protein expression. Blockade of PPAR-g activity by GW9662 remarkably attenuated the inhibitory actions of pioglitazone on atherogenesis, both in diabetic ApoE(-/-) mice and in cultured VSMCs, upon high-glucose challenge. Conclusions: Pioglitazone has a therapeutic effect on atherosclerosis in diabetes, and inhibition of RAGE signaling plays a critical role in mediating the beneficial effects of pioglitazone.