We compared the vascular effects of rosiglitazone versus glyburide and evaluated asymmetric dimethylarginine (ADMA) and oxidative stress as potential mechanisms associated with changes in vascular health in patients with type 2 diabetes mellitus (T2DM). Patients were randomized to 6 months of either rosiglitazone (n = 20) or glyburide (n = 16) in addition to metformin. The following variables were measured pre- and post-treatment: glucose, insulin, homeostasis model assessment (HOMA), hemoglobin A1c (HbA1c), C-peptide, blood pressure, lipids, C-reactive protein (CRP), ADMA, 8-isoprostane, oxidized LDL cholesterol, brachial artery flow-mediated dilation (FMD), endothelium-independent dilation (EID), and brachial and carotid artery stiffness. Rosiglitazone and glyburide treatment resulted in significant and equivalent decreases in glucose (p < 0.0001) and HbA1c (p < 0.0001), with a trend toward decreased HOMA (p = 0.09). Rosiglitazone significantly decreased C-peptide (p < 0.01) with a strong trend toward decreased fasting insulin (p = 0.05). Rosiglitazone reduced CRP compared with glyburide (p = 0.001), but no differences were observed between groups for ADMA or the markers of oxidative stress. Rosiglitazone significantly improved FMD (p < 0.05) with trends toward improvements in carotid artery distension (p = 0.099) and distensibility (p = 0.078). In conclusion, compared with glyburide, rosiglitazone improves endothelial function and CRP in patients with T2DM. These improvements are not associated with reductions in ADMA or markers of oxidative stress.