Abstract Body: Fluctuation in plasma cholesterol due to intermittent statin adherence is common and worsens cardiovascular outcomes. Oxidized phospholipids (oxPL), derived from, or transported by, oxidized low-density lipoprotein (oxLDL) or Lp(a), respectively, play crucial roles in atherosclerotic disease in mice and humans. E06, a naturally produced IgM antibody targeting OxPL, diminishes macrophage (Mφ) uptake of oxLDL in vitro and attenuates atherosclerosis progression in mouse models. Therefore, we hypothesized that OxPL is a causative factor in accelerated atherosclerosis in mice and increased cardiovascular events in people after depressed LDL-C levels are allowed to rise again. To test this, Ldlr^-/- and Ldlr^{-/ -}mice expressing a transgene for E06 (“E06 mice”) were subjected to a plasma cholesterol cycling model (high-low-high), inducing plaque progression (P) for 16 weeks, resolution (PR) after ApoB antisense oligonucleotide (ApoB-ASO) treatment for 4 weeks, and re-progression (PRP) after ApoB-ASO withdrawal for an additional 4 weeks (n≥9/group). As expected, LDL-C rebound accelerated plaque inflammation, assessed by a 30% increase in aortic-root Mφ accumulation in Ldlr^-/- mice (PRP vs. PR: 68.6±4.0 vs. 42.7±7.8%; P=0.004), whereas E06 prevented Mφ rebound during PRP compared to Ldlr^-/- mice (PRP E06 vs. PRP Ldlr^-/-: 46.7±11.2 vs. 68.6±4.0%; P=0.003) and showed no significant change between E06 PR and PRP mice (61.2±11.2% vs. 46.7±4.0; P=0.066). Bioinformatic analysis of plaque Mφ based on single-cell RNA-seq revealed reduced inflammatory pathway activation in PRP E06 mice compared to PRP Ldlr^-/- mice. Bone marrow monocytes from P Ldlr^-/- mice secreted 50% higher IL-6 levels after LPS stimulation compared with P E06 mice (n=3-4, 93.84±12.46 vs. 53.21±13.39 ng/mL, P=0.037), suggesting reduced innate immune priming in E06 mice. Consistent with a higher inflammatory state, P Ldlr^-/- mice exhibited higher circulating white blood cells and monocyte counts than E06 mice (WBC: n=10-12; 4.19±0.68 vs. 3.12±0.79 10³/uL; P=0.004; monocytes: 0.82±0.3 vs. 0.50±0.19 10³/uL; P=0.009). Additionally, patients in the clinical CHORD study at NYU who underwent cholesterol cycling had increased levels of serum OxPL attached to Lp(a) (n=23, P=0.012). In summary, the increased CV events clinically observed in LDL-C cycling may have its mechanistic basis in immune cell priming by OxPL, resulting in exaggerated inflammatory responses in atherosclerotic plaques following LDL-C rebound.