It is well recognised that increased levels of high density lipoprotein (HDL) protect against atherosclerosis and correlate with improved prognosis for vascular disease associated events. While many of the atheroprotective effects of HDL are ascribed to the ability to remove cholesterol from the vasculature through the reverse cholesterol transport system, recent work has shown that HDL may be atheroprotective through its other functions, such as regulation of endothelial adhesion molecule expression, stimulation of endothelial nitric oxide synthase and inhibition of the damaging effects of oxidised low density lipoproteins. Recently, HDL has also been described to interact with circulating cells inhibiting both leukocyte and platelet activation, therefore having further systemic anti-inflammatory functions. This review summarises the studies and models used to examine the anti-inflammatory effects of HDL and details data describing the ability to inhibit leukocyte activation, contributing to the hypothesis that raised HDL is beneficial in the context of inflammation in atherosclerosis. Further, HDL modification in disease and current therapeutic strategies such as reconstituted HDL particles and apoA-I mimetic peptides is discussed to provide insights to the potential applicability of raising HDL to regress cardiovascular disease.