Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E-knockout (apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages (phorbol ester-stimulated THP-1 cells), human serum albumin as a control protein, or HepG2 cells as human control cells, once a week for 4 consecutive weeks. The vehicle phosphate-buffered saline was injected in the non-immunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. While the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by more than 50 % in 16-week old THP-1-immunized apoE-KO mice compared to that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the anti-atherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis.