Background: It is increasingly evident that CD8(+) T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8(+)CD25(+) T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8(+)CD25(+) T cells in experimental atherosclerosis were investigated in this study. Methods and results: CD8(+)CD25(+) T cells were observed in atherosclerotic plaques of apoE(-/-) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8(+)CD25(+) T cells from apoE(-/-) mice. Depletion of CD8(+)CD25(+) from total CD8(+) T cells rendered higher cytolytic activity of the remaining CD8(+)CD25(-) T cells. Adoptive transfer of CD8(+)CD25(+) T cells into apoE(-/-) mice suppressed the proliferation of splenic CD4(+) T cells and significantly reduced atherosclerosis in recipient mice. Conclusions: Our study has identified an athero-protective role for CD8(+)CD25(+) T cells in experimental atherosclerosis. (C) 2013 Elsevier Inc. All rights reserved.