High-density lipoprotein (HDL) appears to have evolved as part of the innate immune system, which in part uses an enhanced oxidative state as a nonspecific means of protecting against many pathogens. In the absence of acute or chronic inflammation, HDL is anti-inflammatory in mice, rabbits, and humans. However, with the onset of a systemic inflammatory state such as what occurs in atherosclerosis, HDL becomes pro-inflammatory, enhancing the inflammatory response. The major apolipoprotein of HDL is apoA-I, which may be altered by oxidative processes in patients with atherosclerosis. As a result, HDL from such patients is less efficient in promoting cellular cholesterol efflux. The ability of HDL to inhibit the inflammatory properties of oxidized phospholipids and low-density lipoproteins is also significantly altered. In mice and monkeys, the administration of an apoA-I-mimetic peptide renders pro-inflammatory HDL anti-inflammatory, improves HDL-mediated cellular cholesterol efflux; in mice, it dramatically inhibits atherosclerosis. Understanding the role of HDL in inflammation may lead to new diagnostic and therapeutic approaches to atherosclerosis and other inflammatory conditions.