Oxidative stress is a result of an imbalanced equilibrium between reactive oxygen species (ROS) generation and their elimination by antioxidants. There is substantial evidence indicating that exacerbated oxidative stress is relevant for the development of atherosclerosis and its associated complications, especially cardiovascular disease (CVD). According to the oxidative modification hypothesis, oxidised low density lipoproteins (LDL) induce atherosclerosis by triggering an inflammatory cascade within the vascular wall. This process can be inhibited or delayed by the antioxidative and antiinflammatory actions of high density lipoproteins (HDL). Clearly, paraoxonase-1 (PON1) is one of the most important contributors to the antioxidative capacity of HDL. Atherogenic dyslipidemia, oxidative stress and inflammatory conditions induce dramatic changes in HDL composition that considerably alters or attenuates HDLs anti-atherogenic effects. Such impairment of HDLs functions provides an important link between oxidative stress and inflammation in the pathogenesis of atherosclerosis. This review summarises and discusses the possible synergistic effects of dyslipidemia, oxidative stress and inflammation in promoting atherosclerosis and its complications, as well as potential benefits of therapeutic modulation of HDLs atheroprotective activity.