The ability of high-density lipoprotein (HDL) to promote cholesterol efflux is thought to be important in its protection against cardiovascular disease. Anti-inflammatory properties of HDL have emerged as additional properties that may also be important. HDL appears to have evolved as part of the innate immune system functioning to inhibit inflammation in the absence of an acute phase response (APR) but functioning to increase inflammation in the presence of an APR. Inbred strains of mice that are genetically susceptible to atherosclerosis have pro-inflammatory HDL, while inbred strains that are resistant to atherosclerosis have anti-inflammatory HDL. In one small study, humans with coronary heart disease (CHD) or CHD equivalents had pro-inflammatory HDL prior to statin therapy and about half continued to have pro-inflammatory HDL after statin therapy despite a profound decrease in plasma lipids. Pro-inflammatory HDL was relatively weak in its ability to promote cholesterol efflux while anti-inflammatory HDL was better in promoting cholesterol efflux. In other studies, oxidative alterations of the major protein of HDL, apolipoprotein A-I (apoA-I), impaired the ability of the apoA-I to promote cholesterol efflux. Thus, HDL structure and function may be more important than HDL-cholesterol levels in predicting risk for cardiovascular disease.