The pro-oxidative and pro-inflammatory pathways in vascular endothelium have been implicated in the initiation and progression of atherosclerosis. In fact, inflammatory responses in vascular endothelium are primarily regulated through oxidative stress-mediated signaling pathways leading to overexpression of pro-inflammatory mediators. Enhanced expression of cytokines, chemokines and adhesion molecules in endothelial cells and their close interactions facilitate recruiting and adhering blood leukocytes to vessel wall, and subsequently stimulate transendothelial migration, which are thought to be critical early pathologic events in atherogenesis. Although interleukin-4 (IL-4) was traditionally considered as an anti-inflammatory cytokine, recent in vitro and in vivo studies have provided robust evidence that IL-4 exerts pro-inflammatory effects on vascular endothelium and may play a critical role in the development of atherosclerosis. The cellular and molecular mechanisms responsible for IL-4-induced atherosclerosis, however, remain largely unknown. The present review focuses on the distinct sources of IL-4-mediated reactive oxygen species (ROS) generation as well as the pivotal role of ROS in IL-4-induced vascular inflammation. These studies will provide novel insights into a clear delineation of the oxidative mechanisms of IL-4-mediated stimulation of vascular inflammation and subsequent development of atherosclerosis. It will also contribute to novel therapeutic approaches for atherosclerosis specifically targeted against pro-oxidative and pro-inflammatory pathways in vascular endothelium.