Regular consumption of fruits and vegetables is strongly associated with a reduced risk of cardiovascular disease (CVD). This effect occurs, in part, because of the plethora of bioactive agents in foods and their subsequent function as antioxidants. Ergothioneine (ERT), a novel antioxidant, is present in edible mushrooms and is not synthesized, but is accumulated, by humans through diet. In this study, we tested whether ERT, a bioactive agent, could interrupt pro-inflammatory induction of adhesion molecule expression associated with atherogenesis. Human aortic endothelial cells (HAECs) were incubated with increasing concentrations of ERT (0.01-10.0 mM) overnight (16 hours) followed by incubation with medium alone or with the pro-inflammatory cytokine interleukin (IL)-1β (5 ng/mL) for 6 hours to induce expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial-leukocyte adhesion molecule (ELAM-1 or E-selectin). ERT at 0.1-0.3 mM significantly (P < .05) reduced VCAM-1, ICAM-1, and E-selectin expression up to 41%. VCAM-1 was suppressed to the greatest extent followed by E-selectin and then ICAM-1. We next tested if binding of preloaded U937 human monocytes to HAECs would be inhibited. U937 binding to HAECs was significantly reduced in IL-1β-stimulated HAECs preincubated with 1 and 3 mM ERT. Unstimulated monolayers demonstrated marginal, but significant, reductions. ERT was not toxic to HAECs at any concentration used. These data provide evidence that ERT found in commonly consumed dietary mushrooms can protect against events observed in atherogenesis, suggesting increased dietary intake of edible mushrooms would be a prudent medicinal means of reducing CVD risk.