Objective: Regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses in atherosclerosis, a chronic autoimmune-like disease. Therefore, in this study, we aimed to investigate the therapeutic effect of amygdalin on atherosclerosis of apolipoprotein E deficient (ApoE(-/-)) mice, and to explore its immune regulatory function by stimulation of Tregs. Methods and results: To evaluate the anti-atherosclerotic effect of amygdalin and for in vivo Treg expansion/activation analysis, ApoE-/- mice received intraperitoneal injections of amygdalin, and this therapy resulted in a comparatively 2-fold decrease in triglyceride (TG), 1.5-fold decrease in total cholesterol (TC) and low density lipoprotein (LDL). By comparing the vessel areas, lumen areas, plaque areas, and aortic plaque coverage percentage, the effects of amygdalin on pre-existing lesions were assessed. Studies on IL-10 and TGF-beta indicated that mice treated with amygdalin had increased expression of Treg-related cytokines. Meanwhile, flow cytometry and real-time PCR data showed that mice treated with amygdalin had higher percentage of CD4(+)CD25(+)Foxp3(+) T cells than untreated mice and increased expression of forkhead box P3 (FOXP3) gene. Conclusion: Our data showed amygdalin could attenuate the development of atherosclerosis by suppressing inflammatory responses and promoting the immunomodulation function of Tregs. The effects of amygdalin ultimately resulted in the enlarged lumen area and the loss of atherosclerotic plaque. All these data indicated the therapeutic potential of amygdalin in preventing and/or treating of atherosclerosis. (C) 2011 Elsevier Inc. All rights reserved.