Atherosclerosis is a complex pathologic process initialed by the formation of cholesterol-rich plaque. Macrophages play a central role in the development of atherosclerosis, specifically in the initial accumulation of cholesterol in the arterial wall. It has been suggested that infection and chronic inflammatory conditions such as periodontitis may influence the atherosclerosis process. Porphyromonas gingivalis, one of the major pathogens involved in periodontitis, has been detected in human atheromas, suggesting that P. gingivalis infection may be associated with atherosclerosis. However, a causal relationship between this pathogen and the disease process has not yet been established. The purpose of the present investigation was to determine whether P. gingivalis could induce macrophages to form foam cells using the murine macrophage cell line (J774) as a model system. For inocula smaller than one bacterium per ten cells, P. gingivalis 381, as well as its lipopolysaccharide (LPS), induced foam cell formation of macrophages when cultured in the presence of human low-density lipoprotein (LDL). Infection of macrophages with increasing doses of P. gingivalis resulted in higher levels of foam cell formation. More than 70% of the cultured macrophages form cholesterol ester droplet-rich cells in the presence of 100 mug/ml of LDL when the inocula was more than 10 bacteria per cell. Low concentrations of P. gingivalis outer membrane vesicles also induced foam cell formation in the presence of LDL. In addition, it was demonstrated that P. gingivalis LPS alone was able to induce macrophage foam cell formation. P. gingivalis and its vesicles not only promoted LDL binding to macrophages but also induced macrophages to modify native LDL, which plays an important role in foam cell formation and the pathogenesis of atherosclerosis. Therefore, P. gingivalis cells or its vesicles released from periodontal lesions into the circulation may deliver virulence factor(s) such as LPS to the arterial wall to initiate or promote foam cell formation in macrophages and contribute to atheroma development.