Atherosclerosis is a major vascular complication of diabetes and the primary cause of mortality in patients with this disease. Inflammation has been implicated in the pathogenesis, progression and complications of both atherosclerosis and diabetes type 2, and these two complex disorders are often found intertwined in the patients. Peroxisome proliferatoractivated receptors-γ (PPARs-γ) are nuclear receptors that have been involved as transcriptional mediators in glucose homeostasis, lipid metabolism, and adipogenesis. PPAR-γ agonists, the thiazolidinediones (TZDs) are antidiabetic drugs that increase insulin sensitivity, lower blood glucose, decrease triglycerides and free fat acids and seem to have antiinflammatory effects as they reduce inflammatory markers and improve cardiovascular risk factors. All the major cell types in the vasculature express PPAR-γ including macrophages and vascular smooth muscle found cells in human atheroma. Activation of PPAR-γ by thiazolidinediones blocks vascular smooth muscle cells growth and migration thus reducing atherosclerosis. Several clinical studies have illustrated the beneficial role of thiazolidinediones in the atherosclerosis process, as they ameliorate endothelial dysfunction, reduce intima media thickness (IMT) in the carotid arteries and the restenosis rate after coronary stent implantation. However, recent trials have raised significant concerns about the deleterious action of thiazolidinediones, particularly rosiglitazone, on the cardiovascular system. Weighing the potential beneficial and harmful role of thiazolidinediones and exploring the possible mechanisms may provide a thorough view about the optimum clinical use of these compounds.