Abstract-Atherosclerosis is increasingly recognized as a chronic inflammatory disease. Although a variety of inflammatory markers (ie, C-reactive protein) have been associated with atherosclerosis and its consequences, it is important to identify principal mediators of the inflammatory responses. One potentially important source of vascular inflammation in atherosclerosis is bacterial endotoxin. Mutations in Toll-like receptor 4 (TLR-4), an integral component of the endotoxin signaling complex, are fairly common in the Caucasian population and have recently been associated with reduced incidence of atherosclerosis and other cardiovascular diseases in some studies. Moreover, epidemiological studies suggest that endotoxemia at levels as low as 50 pg/mL constitutes a strong risk factor for the development of atherosclerosis. Endotoxin concentrations in this range may be produced by a variety of common subclinical Gram-negative infections. In this article, we outline the main elements of the endotoxin signaling receptor complex that initiates proinflammatory signaling (lipopolysaccharide binding protein [LBP], CD14, TLR-4, and MD-2) and discuss how changes in expression of these molecules may affect proatherogenic responses in the vessel wall. We also describe some of the proinflammatory effects of endotoxin that may be relevant to atherosclerosis, and discuss how serum lipoproteins, especially high-density lipoprotein, may modulate endotoxin-induced inflammatory responses. Further, we discuss recent findings suggesting that the lipid-lowering statins may have an additional protective role in blocking at least some of these proinflammatory signaling pathways. Finally, we discuss species diversity with regard to endotoxin signaling that should be considered when extrapolating experimental data from animal models to humans. I n recent years, there has been an increasing recognition of the link between inflammation and atherosclerosis. [1][2][3][4][5][6][7][8] Although markers of chronic inflammation, such as C-reactive protein, are clearly predictive of clinical atherosclerosis, 9,10 the sources of inflammatory responses, and the mechanisms by which inflammation leads to vascular disease, remain to be elucidated. One potentially important source of inflammation is endotoxin (lipopolysaccharide [LPS]), a unique glycolipid that comprises most of the outer leaflet of the outer wall of Gram-negative bacteria (GNB). [11][12][13][14][15] This complex molecule, found exclusively in GNB, consists of a highly variable carbohydrate portion and a unique lipid A region that is highly conserved across many GNB species. Gram-negative organisms colonize the human gastrointestinal, genitourinary, and respiratory tracts and generate endotoxin not only during overt infections but also in common subclinical or chronic conditions such as periodontitis, sinusitis, bronchitis, or diverticulitis. 16 -18 Even in apparently healthy individuals, endotoxin can be detected in human plasma. The Bruneck study provided the first epidemiological e...