Atherosclerosis, a chronic vascular disease accounts for major deaths worldwide. Associations between atherosclerosis and periodontitis have been documented by epidemiological studies. The process underlying P. gingivalis (Pg) infection induced atherogenesis however, is unclear. Macrophage ‘foam cells’ formation is a hallmark for in-vivo atherosclerosis progression. Our studies indicate that a calcium channel, Transient Receptor Potential channel of the vanilloid family 4 (TRPV4) mediates foam cell generation on Pg lipopolysaccharide (PgLPS) stimulation. Also, we observed increased TRPV4 activity (Ca2+ influx) with PgLPS treatment. Genetic deletion of TRPV4 or inhibition by TRPV4 specific chemical antagonist impeded PgLPS-triggered aggravated oxidized LDL (oxLDL) uptake and foam cell formation. Our results mechanistically showed that i) TRPV4 is required for oxLDL uptake, but not its cell surface binding ii) Decreased foam cell formation is independent of CD36 expression. Altogether, our results demonstrate that TRPV4 plays a crucial role in PgLPS-induced exacerbation of oxLDL-mediated macrophage foam cell formation.