Inflammatory mediators such as TNF-α, IL-1β, and IL-8, which can enhance binding of LDL to endothelium and smooth muscle cells and upregulate expression leukocyte adhesion molecules on endothelium during atherogenesis. Lycopene, a natural carotenoid from tomato and other sources, has been shown to inhibit IL-1β-induced ICAM-1 and VCAM-1 expression in human endothelial cells (Martin et al., 2000). However, its action mechanism is still largely unknown. In the present study, we studied the effect of lycopene on TNF-α-induced signaling in human umbilical endothelial cells (HUVECs). TNF-α-induced ICAM-1 mRNA and protein expression in HUVECs was inhibited by lycopene, whereas its expression in smooth muscle was not affected. A gel electrophoresis mobility shift assay (EMSA) further demonstrated that lycopene inhibited TNF-α-induced NF-κB-DNA complex formation. This possibly attributed to that lycopene attenuated TNF-α-induced IκB phosphorylation and NF-κB translocation from cytosol to nucleus. In a functional study, lycopene blocked THP-1 monocyte adhesion to endothelial monolayer, while it exhibited no obvious inhibitory effect on THP-1 monocyte adhesion to various matrix proteins such as collagen, laminin and fibronectin. Taken together, our results for the first time demonstrate that lycopene is able to inhibit TNF-α-induced monocyte-endothelial interaction, ICAM-1 expression and NF-κB translocation, suggesting an anti-inflammatory role of lycopene.