Oxidative stress, induced by reactive oxygen species (ROS), is implicated in the pathogenesis of plaque formation and instability. During this ongoing oxidative process, cells in the vasculature are exposed to the atherogenicity of the plaque; previous studies have suggested that the arterial plaque, apart from being a consequence of the development of atherosclerosis, is also a cause of its progression. Objective: In this study, we challenged this idea by investigating the effect of carotid plaque lipid extract on the human monocyte antioxidant system. Methods and Results: Exposure of monocytes to carotid plaque lipid extract (LE) for up to 72 h resulted in a significant increase in the ROS level (170%), with a simultaneous rise of 177% in glutathione oxidation. Experiments revealed a significant decrease, in the intracellular antioxidant enzyme activity of CAT, GPx and TRxR, (by 17, 33 and 43%, respectively). Although the activity of these enzymes subsequently returned to those of the controls, the levels of ROS did not decrease but rather continued increasing with extended LE exposure. Intriguingly, intracellular SOD activity rose significantly and remained high (176%), implying that endogenously produced H2O2, and not O-2(center dot-)< is the factor that promotes the oxidative stress resulting from the presence of LE. Conclusion: Lipids from the atherosclerotic plaque may contribute to the progression of atherogenic conditions in adjacent regions by weakening the cellular antioxidant system and promoting oxidative stress, mainly through H2O2 production. (C) 2012 Elsevier Inc. All rights reserved.