Various studies have demonstrated an association between chronic bacterial infections and atherosclerotic cardiovascular disease. Porphyromonas gingivalis, which can invade endothelial cells, is one pathogen that may link these disorders. If so, antibiotics that block its invasiveness may ameliorate atherosclerotic plaque progression. To explore the role of invasion of P. gingivalis in inflammation- and infection-associated atherosclerosis, 10-wk-old ApoE+/− mice were fed either a high fat diet or a regular chow diet. All mice were inoculated i.v., once per week for 24 consecutive wk, with either 50 μl of live P. gingivalis (strain 381) (107 CFU); a fimbria-deficient P. gingivalis; or metronidazole before P. gingivalis. Mice were euthanized and evaluated 24 wk after the first inoculation. ApoE+/− mice injected with DPG3 or metronidazole showed significantly fewer atheromatous lesions in the proximal aorta and the aortic tree compared with ApoE+/− mice injected with wild-type P. gingivalis for either diet condition. Serum amyloid A levels were significantly lower in ApoE+/− mice that received either DPG3 or metronidazole before P. gingivalis than from ApoE+/− mice that received P. gingivalis alone. Serum cytokine analysis revealed decreased levels of proinflammatory cytokines in both DPG3-injected and metronidazole/P. gingivalis-treated ApoE+/− mice compared with mice receiving only P. gingivalis, irrespective of diet. P. gingivalis invasion is a critical phenomenon in the progression of atherosclerosis. The present data offer new insights into the pathophysiological pathways involved in atherosclerosis and pave the way for new pharmacological interventions aimed at reducing atherosclerosis.