Systemic inflammation at the development of an acute coronary syndrome (ACS) might alter the high-density lipoprotein (HDL) components and function. .....We analyzed the cholesterol efflux in those ACS (within 72 hours of symptoms [ACS1]) and, again, 3 months later (ACS2). As controls, we used normal subjects without coronary artery disease (CAD) and patients with chronic, stable CAD. The 4 groups were matched for age and HDL cholesterol levels. We used a cell-based efflux system in (3)[H]-cholesterol-labeled J774 macrophages to measure cholesterol efflux from apolipoprotein B-depleted plasma. The present study included 20 patients with ACS. Their mean age was 58 ± 9 years, and the mean HDL cholesterol level was 1.06 ± 0.22 mmol/L (41 ± 9 mg/dl). The ACS1 group showed a marked increase in high-sensitivity C-reactive protein and serum amyloid A, reflecting systemic inflammation. The HDL cholesterol efflux capacity was reduced in ACS1 subjects and remained reduced 12 weeks later and in those with stable CAD. These results suggest that the acute presence of serum amyloid A does not account for the impairment of HDL-mediated cholesterol efflux capacity in the ACS1 group. Little correlation was found between HDL cholesterol and HDL efflux capacity (r = 0.233; p = 0.049), suggesting that HDL cholesterol is a poor marker of HDL function in inflammatory states and CAD. In conclusion, our data support the concept that atherogenic HDL dysfunction and impaired efflux occur in ACS, independent of changes in plasma HDL cholesterol and apolipoprotein A-I levels.