Reactive oxidant species (ROS) seem to play a key role in the atherosclerotic process via a series of molecular changes that lead to macrophage infiltration in the endothelium and eventually to plaque formation. ROS are also implicated in arterial dysfunction via inactivation of nitric oxide, a potent vasodilator and antiaggregating molecule produced by the endothelium. Owing to the relevance of endothelial dysfunction and vascular inflammation in the process of human atherosclerosis, a lot of effort has been directed towards discovering the ROS-generating pathways implicated in the ROS upregulation. Amongst the enzymatic pathways, NADPH oxidase is the most important enzyme responsible for ROS formation in human vessels. Experimental and clinical studies suggested a role for this enzyme in initiation and progression of atherosclerotic disease. The purpose of this review is to analyze whether the basic and clinical studies are consistent with this hypothesis and to point out if determination of NADPH oxidase is useful in the setting of the atherosclerosis to predict its progression and clinical complications.