Abstract Body: Olfactory receptors (ORs), the largest family of G-protein-coupled receptors (GPCRs), are increasingly recognized as key regulators of inflammation, with expression observed in macrophages and monocytes. While certain ORs, such as Olfr2, have been linked to inflammation and atherosclerosis modulation in mice, the roles of many other ORs remain unexplored. Using transcriptomic analysis of macrophages from the aortas of atherosclerosis-prone Apoe^-/- mice, we identified Olfr519, a receptor for hydro-cinnamyl-propionate (PP), a detectable ligand in mice. Olfr519 expression was confirmed in macrophages through flow cytometry in mouse aortas and bone marrow-derived macrophages (BMDMs). PP stimulation (10μM) triggered Ca2+ flux and released IL-1β and IL-1α in BMDMs, with effects dependent on Olfr519, as shown by siRNA knockdown and experiments in Olfr519 knockout (KO) mice. The human ortholog, OR10A3, is expressed in human monocyte-derived macrophages (hMDMs), with expression upregulated by lipopolysaccharide (LPS) and PP. Knockdown of OR10A3 significantly reduced IL-1β release in response to PP in hMDMs. In vivo, intraperitoneal PP injections (10 mg/kg) accelerated atherosclerosis in Apoe^-/- mice, while bone marrow transfer from Olfr519^-/- mice into LdlR^-/- mice fed a high-cholesterol diet reduced atherosclerosis progression compared to wild types. These findings establish Olfr519 as a new critical modulator of macrophage-driven inflammation.