OBJECTIVES: We sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis. BACKGROUND: The PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential effects required to induce plaque regression and stabilization. METHODS: Atherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC) diet. The rabbits were randomized into a continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study. RESULTS: All groups had a similar vessel wall area by MRI (8.45 ± 0.65 mm2, p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 ± 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (-2.5 ± 3% and -4.5 ± 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (-12 ± 4% [p < 0.05] and -22 ± 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions. CONCLUSIONS: Our data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin.