Background: One of the suggested mechanisms of increased cardiovascular risk in postmenopause is a loss of the antioxidant effects of estrogens. It has been shown that classical cardiovascular risk factors increase oxidative stress on the arterial wall, and that endothelial cells react to this insult by increased expression of cellular adhesion molecules (CAM), which in turn are markers of arterial wall inflammation. Methods: A randomized, placebo-controlled, double-blind study was performed in 60 postmenopausal women with high cardiovascular risk profiles, but free from clinical atherosclerotic disease. Patients were randomized to either antioxidant supplementation (using a combination of natural antioxidants; n = 30) or placebo (n = 30), and followed for 12 weeks. The concentrations of the adhesion molecules sVCAM-1 and sICAM-1 were measured by ELISA at baseline and at the end of the study, as well as total cholesterol, LDL, HDL, triglycerides and blood pressure. Results: 27 women in the antioxidant supplementation group and 29 on placebo completed the study. At baseline, there were no significant differences in measured parameters between the groups: sICAM-1 concentrations were 341.8 ± 116.9 vs. 349.9 ± 104.6 ng/ml (active treatment vs. placebo; p = n.s.) and sVCAM-1 concentrations were 780.5 ± 325.8 vs. 761.0 ± 333.7 ng/ml (p = n.s.). In contrast, at the end of the study, sICAM-1 concentrations were 301.6 ± 56.0 vs. 356.0 ± 134.8 ng/ml (active treatment vs. placebo; p = 0.053) and sVCAM-1 concentrations were 656.0 ± 326.5 vs. 818.5 ± 381.0 ng/ml (p = 0.04). There were no significant differences between or changes within the groups in measured cholesterol and blood pressure. Conclusion: Antioxidant supplementation reduces serum concentrations of endothelium-derived adhesion molecules sICAM-1and sVCAM-1 in postmenopausal women with high cardiovascular risk profiles.