Type 2 diabetes mellitus (T2DM) is associated with an increased risk of micro- and macrovascular complications, causing considerable morbidity and mortality. Endothelial dysfunction and insulin resistance have been strongly associated with reduced vascular reactivity in T2DM. We investigated the effect of the insulin-sensitizing antidiabetic agent rosiglitazone at a dose level of 8 mg/day on in vivo skin nitric oxide (NO) production and blood flow in the foot in a 16-week, randomized, double-blind, placebo-controlled crossover to open-label, single-blind study in patients with T2DM. NO production was assessed using an amperometric meter inserted directly into the skin. Skin perfusion was studied using laser Doppler techniques in response to local warming. Ten patients completed the study. NO production was significantly increased by rosiglitazone compared with baseline after 8-16 weeks of treatment (from 61.6+/-13.5 to 85.3+/-6.4 nM, P<.05 in response to warming). Fasting serum C-peptide levels were significantly reduced (P<.05) compared with baseline following rosiglitazone (4.78+/-1.19 ng/dl at Week 2 compared with 3.63+/-0.72 ng/dl after rosiglitazone treatment at Week 16), correlating inversely (r=-.65, P=.08) with the increase in NO production. Skin perfusion increased after 16 weeks of rosiglitazone treatment (P=ns). This is the first study to show that rosiglitazone attenuates the effects of T2DM on NO production, a marker of endothelial function, in vivo. This provides further evidence for the beneficial effects of rosiglitazone on nontraditional cardiovascular risk factors associated with T2DM.