Background: Inflammatory stimuli induced by NF-kB drive atherosclerotic lesion formation. The epigenetic P300/CBP associated factor (PCAF) post-transcriptionally acetylates FoxP3, which is required for regulatory T-cell (Treg) differentiation and immune modulation. We hypothesize that PCAF deficiency affects atherosclerosis via regulation of regulatory Tregs.Method: ApoE3*Leiden (n = 13) and ApoE3*LeidenxPCAF−/− (n = 13) were fed a high-fat diet (HFD) containing 1.25% cholesterol. Systemic FoxP3+ T cells were measured every 4 weeks by flow cytometry (n = 6). After 5-months of HFD, mice were euthanized, and hearts and blood were collected. IL-6 and TNFα concentrations were measured in plasma to identify systemic inflammatory responses. Compositional and morphometrical analyses were performed on the atherosclerotic lesions in the aortic sinuses.Results: After 5 months of HFD, plasma cholesterol concentrations were not different for ApoE3*LeidenxPCAF−/− compared to ApoE3*Leiden mice. Expression of FoxP3 by systemic CD4+ T cells decreased 1.8 fold in ApoE3*LeidenxPCAF−/− after 5 months HFD and remained significantly reduced after 5 months of HFD. Systemic TNFα and IL-6 concentrations were comparable, whereas the atherosclerotic lesion size in ApoE3*LeidenxPCAF−/− mice was increased by 28% compared to ApoE3*Leiden mice. In atherosclerotic lesions, no differences were observed in macrophage differentiation or VSMC content, although a small increase in collagen was identified.Conclusion: Our data show that PCAF deficiency resulted in a decrease in circulatory FoxP3+ regulatory T cells and ameliorated atherosclerotic lesions with no differences in systemic inflammation or macrophage differentiation in the atherosclerotic lesions. This suggests that PCAF regulates atherosclerosis via modulation of FoxP3+ regulatory T cell differentiation.