Abstract Body: Atherosclerosis is driven by monocyte recruitment and sustained by dysfunction of macrophages (Mφ) within the arterial wall. A defining pathogenic event is the accumulation of modified low-density lipoproteins (LDL), particularly oxidized LDL (oxLDL), which drives Mφ into a lipid-laden foam cell state that adopts a pro-inflammatory phenotype, thus accelerating lesion growth. However, the molecular mechanisms governing this remain incompletely defined. Here, we identify Olfr2/OR6A2 as a critical regulator of pro-inflammatory foamy phenotype transition. Genetic ablation of Olfr2 markedly reduced atherosclerotic lesion burden and lipid accumulation in plaque Mφ in Apoe^-/- mice fed a high-fat diet for 10 weeks. Importantly, this protective phenotype was recapitulated by inhibiting Olfr2 using its antagonist, citral. Consistent with in vivo findings, Olfr2 deficiency attenuated lipid accumulation in bone marrow-derived Mφ (BMDMs), as demonstrated by reduced BODIPY and Oil Red O staining. This effect was specific for oxLDL, indicating a ligand- and pathway-specific mechanism. Olfr2 deletion reduced oxLDL uptake without altering oxLDL binding or CD36 expression, suggesting a post-binding step of oxLDL internalization rather than CD36 availability. Immunofluorescence analyses revealed co-localization of Olfr2 with CD36 and lipid-rafts, supporting a coordinated spatial organization of these receptors within membrane microdomains. Mechanistically, blockade of Olfr2-dependent Ca++ influx with diltiazem significantly reduced oxLDL internalization, indicating that oxLDL engagement of CD36 cooperates with Olfr2 signaling to trigger Ca++ flux required for efficient oxLDL uptake. Bulk transcriptomic profiling of oxLDL-treated Mφ further revealed that Olfr2 deficiency promotes an anti-inflammatory Mφ state, characterized by enrichment of reparative markers (i.e., Mrc1, Il4ra, Cd28) and suppression of inflammatory and stress-associated genes (i.e., Jak2, Il1r1, Il7, Cd47). Inhibition or knockdown of OR6A2, the human ortholog of Olfr2, similarly reduced lipid accumulation and inflammatory gene expression in human Mφ. Spatial transcriptomic analysis of human atherosclerotic plaques identified OR6A2⁺ Mφ enriched for foam-cell–associated genes (MMP9, SPP1, GPNMB) within diseased regions, supporting translational relevance. Together, these findings establish Olfr2/OR6A2 as a key molecular node linking oxLDL uptake to Ca++ driven inflammatory signaling in foamy Mφ.