Oxidative stress and vascular inflammatory response are key mediators of endothelial dysfunction that leads to cardiovascular diseases. A novel peptide, IRW, was previously characterized from egg protein with angiotensin converting enzyme inhibitory activity. The purpose of the study was to investigate the effects and molecular mechanisms of IRW on regulating inflammatory response in endothelial cells. The results showed that tumor necrosis factor-α (TNF-α) significantly increased the protein levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1), whereas pretreatment with IRW inhibited TNF-α-induced increases of ICAM-1, VCAM-1, and MCP-1 production in a concentration-dependent manner. IRW also reduced the levels of superoxide ions in the presence and absence of TNF-α. These results indicate the potential role of IRW in preventing cardiovascular disease as a functional food ingredient or nutraceutical.