Aim To evaluate whether heat shock protein 60(HSP60) oral administration could induce antigen-specific CD4+CD25+ regulatory T cells and its effect on the formation of atherosclerotic plaque in hypercholesterolemic apolipoprotein(Apo) E-/-mice. Methods At 8 weeks of age,12 male Apo E-/-mice were divided into two groups that were orally administrated PBS plus HSP60 and only PBS separately for 5 days,and a high-cholesterol diet was started 5 days after the last treatment for 12 weeks,at which time pathological analysis of plaque was performed,percentage of CD4+CD25+ regulatory T cells in splenocytes were analyzed by FCAS,proliferation response of splenocytes to HSP60 was detected and cytokines in the superanant were determined by ELISA. Results Compared with control animals,oral tolerance to HSP60 resulted in a significant decrease in the size of atherosclerotic plaques,and had a significant increase in CD4+CD25+ regulatory T cells in spleen.Specifical proliferation response of CD4+CD25+ regulatory T cells in splenocytes to HSP60 was significantly suppressed and the level of TGF-β and IL-10 in the superanant increased while IFN-γ decreased significantly. Conclusion HSP60 oral tolerance can induce antigen-specific CD4+CD25+ regulatory T cells which in turn attenuates the progression of atherosclerotic plaque.This provides a new immunologic approach for the prevention of atherosclerosis.