Abstract Body (Do not enter title and authors here): Background: Sex, cholesterol and immune responses play significant roles in atherosclerosis development. Cholesterol lowering and global anti-inflammatory therapy have therapeutic limitations. Immune modulation with ApoB-100 peptide-based nanoparticles, named P210-PAM, reduced atherosclerosis in ApoE^–/– mice carrying human HLA-A*0201 allele (A2Kb-Tg) when administered before significant atherosclerosis formed. In this study, we investigated the potential interaction among sex, cholesterol and immune responses in modulating atherosclerosis with P210-PAM therapy. Methods: A2Kb-Tg mice of both sexes fed high fat diet for 8 weeks were injected s.q. 3x with P210-PAM at 2–3-week intervals with or without change to normal chow at the second injection time point. PBS injections served as controls. Aortic atherosclerosis, splenic monocyte/macrophage and T cells were evaluated. Results: P210-PAM therapy without diet change had no effect on established atherosclerosis in both sexes (Table). P210-PAM therapy in female mice with diet change significantly inhibited growth of established atherosclerosis (Table) and reduced IL1R1 expression on splenic monocyte/macrophages (106.1±16.9, N=12, vs 137.5±23.6, N=13; P<0.05) with increased splenic CD8⁺ T_CM (25.6±7.8%, N=13, vs 19.5±4.9%, N=14; P<0.05). P210-PAM therapy with diet change had no effect in male mice (Table). Conclusion: P210-PAM therapy with cholesterol lowering has a sex-specific effect on atherosclerosis highlighting the potential interaction among sex, cholesterol and immune responses in modulating atherosclerosis.