Abstract Body: Atherosclerosis is a lipid-driven immuno-metabolic and inflammatory disorder characterized by plaque formation in the arterial intima, primarily due to the accumulation of modified low-density lipoproteins (LDL) such as oxidized LDL. After oxLDL exposure macrophages acquire a lipid-loaded “foamy” phenotype characterized by the expression of Trem2, which modulate oxLDL uptake, esterification, and storage. When overwhelmed, foamy macrophages can switch to a proinflammatory state, leading to disease progression. This mechanism is still unknown. Here, we described that Olfr2, whose depletion has been shown to be protective in atherosclerosis, is involved in the proinflammatory switch of foam cells that leads to atherosclerosis progression. We found that the lack of Olfr2 in BMDMs mediates less oxLDL accumulation, significantly reducing the lipid marker (BODIPY) signal compared to WT. Gene expression analysis showed significant upregulation of oxLDL processing genes like Abcg1, Abca1, and Trem2 and downregulation of Lox1 in oxLDL stimulated Olfr2 KO BMDMs. Moreover, upregulation of anti-inflammatory genes such as IL10, and IL1R2 in oxLDL-treated Olfr2 KO BMDMs compared to WT BMDMs suggests that Olfr2 KO BMDMs may have an anti-inflammatory phenotype and critical role of Olfr2 signaling in determining the inflammatory phenotype of foamy macrophages. Upregulation of Trem2 in Olfr2 KO BMDMs after oxLDL stimulation was confirmed by flow cytometry. Similarly, citral, a known Olfr2 inhibitor, upregulated Trem2 after oxLDL incubation delineating Olfr2 and Trem2 crosstalk might help to identify a potential target to lower the disease burden of atherosclerosis in humans.