The accumulation of epidemiologic, pathologic, and animal model studies suggests that periodontal infection may be a contributing risk factor for atherosclerosis. The Toll-like receptor-4 (TLR4) signaling pathway plays an important role in the initiation and progression of periodontitis-associated atherosclerotic disease. We postulate that suppression of TLR4 signaling pathway can be an effective treatment for atherosclerosis. These strategies include prevention of ligand binding to TLR4, blocking the interactions of TLR4s and adaptors in signaling pathways, blocking the enzymes in signaling pathways, and immunostimulation with vaccine adjuvants. However, we should be aware that there may be unknown risks about the new technologies and these drugs, which may cause some unknown side effects in long-term administration.