We have investigated the effect of atorvastatin on the endothelial function of patients with diabetes and subjects at risk for type 2 diabetes in a 12-wk, prospective, randomized, placebo-controlled, double-blind clinical trial. The flow- mediated dilation (FMD; endothelium dependent) and nitroglycerin-induced dilation (endothelium independent) in the brachial artery and the vascular reactivity at the forearm skin were measured. FMD improved in the atorvastatin-treated, at-risk subjects [median (25-75 percentile), 7.2% (2.9-9.6%) at exit visit vs. 6.6% (2.9-9.5%) at baseline; P < 0.05]. A similar improvement of FMD was found in atorvastatin-treated diabetic patients [median (25-75 percentile), 5.6 (3.9-7.9) at exit visit vs. 4.2 (3.2-7.2) at baseline; P = 0.07]. No changes were observed in nitroglycerin-induced dilation and the microcirculation reactivity measurements in either group. In the at-risk group, there was a decrease in the C-reactive protein [median (25-75 percentile), 0.12 mg/dl (0.07-0.27 mg/dl) at exit visit vs. 0.24 mg/dl (0.07-0.35 mg/dl) at baseline; P < 0.05] and TNF alpha [median (25-75 percentile), 2.6 pg/ml (1.8-4.1 pg/ml) at exit visit vs. 4.4 pg/ml (3.6-6.0 pg/ml) at baseline; P < 0.05] in the atorvastatin-treated patients, whereas in the diabetes group, a decrease in endothelin-1 (mean +/- SD, 0.97 +/- 0.29 pg/ml at exit visit vs. 1.19 +/- 0.42 pg/ml at baseline; P < 0.05) and plasminogen activator inhibitor-1 [median (25-75 percentile), 18 ng/ml (9-24 ng/ml) at exit visit vs. 27 ng/ml (7-41 ng/ml) at baseline; P < 0.05] were observed. We conclude that atorvastatin improves endothelial function and decreases levels of markers of endothelial activation and inflammation.