Objectives: EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease [EUROPA] demonstrates reduction in cardiovascular mortality and myocardial infarction for a possible vascular and antiatherosclerotic effect of angiotensin-converting enzyme (ACE) inhibition with perindopril. Our objective was to study the effect of perindopril on endothelial function and to verify its link to risk and occurrence of cardiovascular events. Methods: Blood from 1200 EUROPA patients was withdrawn at baseline and after 1 year of treatment with either perindopril or placebo to measure von Willebrand factor and from 45 healthy subjects and 87 EUROPA patients to study endothelial function at the cellular level by cultivating in vitro human umbilical vein endothelial cells. In this setting, we determined protein expression/activity of endothelial nitric oxide synthase and the rate of apoptosis. Plasma levels of angiotensin II, bradykinin, tumor necrosis factor α, and nitrite/nitrate were also measured. Results: The occurrence of cardiovascular events was related to von Willebrand factor at baseline (P = 0.013) that also significantly decreased after 1 year's treatment (P < 0.001). Perindopril upregulated 19% and 27% protein expression/activity of endothelial nitric oxide synthase (P < 0.05) as well as reduced the rate of apoptosis by 31% (P < 0.05). There was also a significant reduction in levels of angiotensin II, increase in bradykinin, reduction in tumor necrosis factor α, and increase in nitrite/nitrate (P < 0.05 for all). Conclusions: Abnormal endothelial function occurs in patients with coronary artery disease, and this can be counteracted by angiotensin-converting enzyme inhibition with perindopril. These effects could contribute, at least in part, to explaining the results of the main EUROPA Study. © 2006 European Society of Cardiology. Chemicals / CAS: angiotensin II, 11128-99-7; bradykinin, 58-82-2, 5979-11-3; dipeptidyl carboxypeptidase, 9015-82-1; endothelial nitric oxide synthase, 503473-02-7; icatibant, 130308-48-4, 138614-30-9; nitrate, 14797-55-8; nitrite, 14797-65-0; perindopril, 82834-16-0; von Willebrand factor, 109319-16-6; Angiotensin II, 11128-99-7; Angiotensin-Converting Enzyme Inhibitors; Biological Markers; Bradykinin, 58-82-2; Nitric Oxide Synthase Type III, EC 22.214.171.124; Nitric Oxide, 10102-43-9; Perindopril, 82834-16-0; Tumor Necrosis Factor-alpha; von Willebrand Factor.