Atherosclerosis is the main underlying cause of cardiovascular disease and stroke, two major health concerns worldwide. Atherosclerotic lesion progression is driven by pro-inflammatory immune responses. Previous reports have indicated that the 40kDa Major Outer Membrane Protein (MOMP) of the gram negative intracellular bacterium Chlamydophila pneumoniae may have immunomodulatory properties and promote a Th2 mediated immune response. This type of response is predominantly antiinflammatory and protective in the context of atherosclerosis. Therefore, we studied the effects of rMOMP and MHC class II restricted peptides derived from its amino acid sequence on the immune response and atherosclerosis development. We first characterised the effects of rMOMP and the peptides in vitro by treating murine peritoneal macrophages, alone and in co-culture with T cells, with different concentrations of the antigens. Surface marker expression was measured by flow cytometry, and we found that rMOMP, Peptide 3 and Peptide 4 prevented activation of macrophages while Peptides 3 and 4 also prevented T cell activation and induced a regulatory T cell (Treg) phenotype. In vivo studies in C57B1/6 wt and apoE-/- mice showed that immunisation with Peptides 2-4 induced FoxP3+ Treg and IL-10 secretion after 6 weeks. In addition, during 12 week immunisation protocols in apoE-/- mice, Peptides 2-4 increase plasma levels of IL-4, IL-10, TGF-β and IFNγ. Histological analysis of aortic sinus sections from immunised animals showed that rMOMP increased collagen and elastin deposition in the plaque, which indicates a more stable plaque phenotype, while Peptide 2 reduced plaque size. Peptides 3 and 4 also reduced plaque size while simultaneously increasing collagen and elastin deposition. Therefore, we conclude that the atheroprotective effects observed for rMOMP and Peptides 2-4 are mediated through immunomodulation and the promotion of a predominantly antiinflammatory response. In addition, Peptides 3 and 4 are strong candidates for further development as potential anti-atherogenic treatments.