ABSTRACT Many lines of evidence support the proposal that inflammation is of central importance in atherogenesis. In humans, a chronically elevated circulating level of C-reactive protein (CRP), a positive acute-phase reactant, appears to be an independent risk factor for cardiovascular disease. This observation has led to an explosion of interest in the role of inflammatory proteins in atherosclerosis. In this review, we focus on the potential role in the pathogenesis of human vascular disease of inflammation-induced proteins that are carried by lipoproteins. Serum amyloid A (SAA) is transported in the circulation predominantly on high density lipoprotein (HDL), and levels of this protein increase markedly during acute and chronic inflammation in both animals and humans. Elevated levels of SAA appear to predict the risk of cardiovascular disease in humans. Recent animal studies support the proposal that this acute-phase protein plays a role in atherogenesis. Evidence is accruing that secretory phospholipase A2, an HDL-associated protein, and platelet factor acetylhydrolase (PAF-AH), a protein associated predominantly with low density lipoprotein (LDL) in humans and HDL in mice, might also play roles both as markers and mediators of human atherosclerosis. In contrast to positive acute-phase proteins, which increase in abundance during inflammation, negative acute-phase proteins have received less attention. Apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, decreases during inflammation. Recent studies also indicate that HDL is oxidized in patients with established atherosclerosis. These alterations may limit the ability of apolipoprotein A-I to participate in reverse cholesterol transport. Paraoxonase-1 (PON1), another HDL-associated protein, also decreases during inflammation. PON1 clearly is atheroprotective in animal models of hypercholesterolemia. Controversy over its utility as a marker of human atherosclerosis may reflect the fact that enzyme activity rather than blood level (or genotype) is the major determinate of cardiovascular risk. Low levels of PON1 seen with inflammation may promote atherosclerosis. Thus, multiple lipoprotein-associated proteins that change markedly in concentration during acute and chronic inflammation may serve as markers of clinically significant cardiovascular disease. In future studies, it will be important to determine whether these proteins play a causal role in atherogenesis.