Among the several pathological events that lead to the formation of an atheromatous lesion, endothelial cell damage, smooth muscle cell proliferation, and foam cell formation, are considered as particularly significant. In this review we summarize data suggesting that immunological and microbial factors may cause, directly or indirectly, these pathological events. Binding of immunocomplexes to endothelial cells, phagocytic cells, platelets, or erythrocytes could be the starting point for a variety of circuits leading to endothelial cell cytotoxicity and to the release of a variety of mediators, including cell proliferative factors. Endothelial cell toxicity could also be induced, directly or indirectly, by endotoxin; however, the possibility that endotoxin and other microbial factors may induce abnormalities in lipid metabolism at the monocyte/macrophage level which eventually result in intracellular accumulation of cholesterol (particularly if cholesterol levels are elevated) is specially attractive as a potential pathogenic mechanism. The various pathologic pathways discussed in this review appear plausible on the basis of our current knowledge and point to the need to investigate the potential role of infectious processes, autoimmune reactions, and administration of antigenic compounds as possible risk factors for the development of atherosclerosis.