Interleukin-8 (IL-8), a member of CXC chemokine family, has been found to play an important role in the pathogenesis of atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha) is involved in the development and progression of atherosclerosis as well. In this study, we investigated whether and how azelnidipine, a newly developed long-acting calcium antagonist, could inhibit TNF-alpha-induced IL-8 expression in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly increased intracellular reactive oxygen species (ROS) generation in HUVEC, which was completely blocked by azelnidipine or apocynin, an inhibitor of NADPH oxidase. Azelnidipine also completely prevented TNF-alpha-induced increase in NADPH oxidase activity in HUVEC. Further, azelnidipine was found to significantly inhibit activator protein-1 (AP-1) promoter activity and IL-8 expression in TNF-alpha-exposed HUVEC. An inhibitor of AP-1, curcumin, or an anti-oxidant, N-acetylcysteine, also inhibited the TNF-alpha-induced IL-8 expression in HUVEC. These results demonstrated that azelnidipine inhibited TNF-alpha-induced IL-8 expression in HUVEC by blocking NADPH oxidase-mediated ROS generation and subsequent AP-1 activation. Our present study suggests that azelnidipine may play a protective role in the development and progression of atherosclerosis through its anti-oxidative properties.