Background: Advanced glycation end products (AGEs) are assumed to be involved in the development of premature atherosclerosis in diabetic patients, and it has recently been suggested that AGEs play a role in the atherosclerotic process in general. No study has examined the effect of medical intervention on circulating AGEs. Objective: To investigate whether angiotensin-converting enzyme (ACE) inhibitor therapy can influence the circulating levels of AGEs. Methods: Forty-two patients (35 men, 7 women, mean age ± SD 66.5 ± 6.0 years) participating in the Heart Outcomes Prevention Evaluation (HOPE) study were examined. Of these, 24 had been randomized to treatment with the ACE inhibitor ramipril and 18 to placebo at the start of the study. Serum levels of AGEs were measured with a polyclonal anti-AGE antibody, using a competitive immunoassay, in samples obtained from the patients at baseline and after 54 months of follow-up. Results: The serum AGE levels (median and 5th to 95th percentile in parentheses) increased significantly in the placebo group from 4.6 (0.3–17.2) U/ml to 7.7 (4.3–23.2) U/ml (p < 0.005) and in the ramipril group from 5.8 (2.7–14.1) U/ml to 7.2 (2.4–21.0) U/ml (p < 0.005). The increase of serum AGEs was significantly lower in the ramipril group than in the placebo group (p < 0.05). Conclusions: The serum levels of AGEs increased in high-risk patients with coronary artery disease over a period of 4.5 years. As compared with placebo, ramipril gave a lower increase of serum AGEs. Interference with AGEs may be a mechanism by which ACE inhibitors have a protective effect in the development of atherosclerosis.