To determine whether pioglitazone influences endothelial function directly, we examined in a randomized, crossover, placebo-controlled, double-blind trial the effects of 4 weeks of pioglitazone treatment in 20 male type 2 diabetic patients. We conclude that short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of significant beneficial changes in plasma levels of insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes. Pioglitazone, a PPARgamma agonist, not only improves insulin resistance and glycemic control but may also have additional beneficial vascular effects in patients with type 2 diabetes. Low-grade inflammation, free fatty acids, and adiponectin may play a role in modulation of vascular function. We studied the effect of 4 weeks of pioglitazone treatment on endothelial function, metabolic changes, and C-reactive protein in patients with type 2 diabetes. A randomized, crossover, placebo-controlled, double-blind trial was performed in which pioglitazone 30 mg once daily was administered to 20 patients with type 2 diabetes on oral antihyperglycemic agents for 4 weeks. Shear stress-induced flow-mediated dilation (FMD) of the brachial artery was used as outcome parameter for vascular function. Brachial artery endothelial function was significantly increased by pioglitazone treatment compared with placebo (FMD 5.4 +/- 0.5% versus 3.1 +/- 0.5%, P = 0.001). Endothelium-independent vasodilation was not different between the 2 study periods. Pioglitazone treatment reduced insulin, FFA, and C-reactive protein concentrations compared with placebo (18.3 +/- 2.4 versus 14.8 +/- 2.1 mU/L, P = 0.03; 641 +/- 46 versus 542 +/- 33 mumol/L, P = 0.04; and 3.5 +/- 0.6 mg/L versus 2.6 +/- 0.5 mg/L, P = 0.01; respectively). A significant increase in plasma adiponectin concentration (3.95 +/- 0.57 microg/mL versus 7.59 +/- 0.95 microg/mL, P = 0.002) was also observed. No correlations were found between these metabolic changes and the improvement of conduit artery endothelial function. Short-term pioglitazone treatment ameliorates endothelial dysfunction in conduit arteries irrespective of changes in insulin, FFA, adiponectin, or CRP in type 2 patients with diabetes.