Background: The effect of pioglitazone and rosiglitazone on endothelial dysfunction has not been compared. The purpose of our study was to compare the effect of pioglitazone and rosiglitazone on atherosclerotic and inflammatory markers, especially in terms of the endothelial dysfunction, in patients with metabolic syndrome. Methods: In this prospective, randomized, open-label, crossover trial, 44 patients with metabolic syndrome were assigned to receive pioglitazone (15mg/day) or rosiglitazone (4mg/day) for 8 weeks. A wash-out period of 6 weeks was included for the cross-over time. The various atherosclerotic and inflammatory markers such as flow-mediated dilation (FMD), pulse wave velocity (PWV), adiponectin, interleukin(IL)-6, IL-18 and high sensitivity C-reactive protein (hsCRP) were evaluated. Results: Both pioglitazone (6.1 짹 2.7 at baseline and 7.8 짹 3.2 at follow-up, p<0.05) and rosiglitazone (6.4 짹 4.8 at baseline and 7.6 짹 4.0 at follow-up, p<0.05) treatments significantly improved FMD (40.2 짹 48.7% and 36.7 짹 56.9%, respectively), the nitroglycerin-induced vasodilatation (46.6 짹 119.1% and 32.4 짹 22.6%, respectively) and serum adiponectin level (97.6 짹 34.2% and 76.7 짹 18.5%, respectively) compared with baseline. However, no significant differences were found between the two treatments. The changes in PWV, IL-6 and hsCRP demonstrated no significant differences between the two treatments. On the other hand, IL-18 level was decreased only with pioglitazone treatment, and total serum cholesterol and LDL cholesterol levels were increased only with rosiglitazone treatment. Conclusions: Both pioglitazone and rosiglitazone treatments showed a similar effect on FMD in patients with metabolic syndrome, in spite of the differences in lipid profiles and IL-18 levels with the two treatments.