Psoriasis, a chronic inflammatory skin disease, has been linked to increased myocardial infarction and stroke. Functional impairment of HDL may contribute to the excess cardiovascular mortality of psoriatic patients. However, data available regarding the impact of psoriasis on HDL composition and function are limited. HDL from psoriasis patients and healthy controls was isolated by ultracentrifugation and shotgun proteomics, and biochemical methods were used to monitor changed HDL composition. We observed a significant reduction in apoA-I levels of HDL from psoriatic patients, whereas levels of apoA-II and proteins involved in acute-phase response, immune response, and endopeptidase/protease inhibition were increased. Psoriatic HDL contained reduced phospholipid and cholesterol. With regard to function, these compositional alterations impaired the ability of psoriatic HDL to promote cholesterol efflux from macrophages. Importantly, HDL-cholesterol efflux capability negatively correlated with psoriasis area and severity index. We observed that control HDL, as well as psoriatic HDL, inhibited dihydrorhodamine (DHR) oxidation to a similar extent, suggesting that the anti-oxidative activity of psoriatic HDL is not significantly altered. Our observations suggest that the compositional alterations observed in psoriatic HDL reflect a shift to a pro-inflammatory profile that impairs cholesterol efflux capacity of HDL and may provide a link between psoriasis and cardiovascular disease.