AIMS: To investigate whether activation of atheroprotective peritoneal B1a cells by apoptotic cells or phosphatidylserine liposomes (PSLs) can enhance their protective actions during atherosclerosis development. METHODS AND RESULTS: Male apolipoprotein E-knockout (ApoE-/-) mice were treated with apoptotic cells or PSLs at the beginning of 8-week high-fat diet. Intraperitoneally administered apoptotic cells attenuated atherosclerosis in hypercholesterolemic ApoE-/- mice by 53 and macrophage accumulation by 52 , effects mimicked by administering PSLs and abolished by B1a cell depletion by splenectomy. These effects were associated with reduced lesion CD4+ and CD8+ T cells, mRNAs of MCP-1, VCAM-1, TNF-alpha, IL-1beta, IL-12, and IL-18 while anti-inflammatory TGF-beta mRNA levels doubled. Apoptotic cells or PSLs increased B1a lymphocytes including TIM-1+ B1a cells in vivo and in vitro while other lymphocyte populations were unaffected. Total plasma IgM, anti-leucocyte, anti-CD3, anti-CD4, and anti-oxLDL IgM were elevated. IgM in atherosclerotic lesions was also elevated and this was associated with reduced lesion MDA-LDL (oxLDL), apoptotic cells and necrotic core size. These effects of activating B1a cells could be attributed to B1a-derived polyreactive IgM deposited in lesions that reduce inflammatory cytokines by lowering lesion ox-LDL via anti-oxLDL IgM, T-cells via anti-leucocyte, anti-CD3, and anti-CD4 IgM, apoptotic cells and necrotic core size via IgM binding to apoptotic cells and enhancing phagocytosis, which also elevates anti-inflammatory cytokines. CONCLUSION: Targeting B1a cell activation by PSLs may be a potentially potent therapeutic strategy to attenuate atherosclerosis and reduce the incidence of atherosclerosis-dependent myocardial infarction and stroke.