COX-2 contributes to local inflammation in atherosclerotic lesions. Regulatory T cells (Tregs) enhance the stability of atherosclerotic plaques. The aim of this study was to detect the potential relationship between Tregs and COX-2 in vulnerable plaques. Thirty ApoE ^−/− mice were fed a high-fat diet, and a silastic perivascular collar was placed around the right common carotid artery to induce vulnerable plaques. Eight weeks after collar placement, the mice were divided randomly into three groups: control, PBS, and Treg groups. Four weeks later, the right common carotid arteries were collected to detect the expression of COX-2. The results showed that Tregs significantly suppressed the expression of COX-2 in vulnerable plaques. In an in vitro experiment, RAW264.7 cells were divided randomly into three groups, which were precultured without T cells or with CD4 + CD25- T cells or Tregs for 48 h with an anti-CD3 antibody; then the cells were stimulated with LPS for 24 h. The RAW264.7 cells were harvested for RT-PCR and western blot assays and the results showed that Tregs downregulated COX-2 expression in RAW264.7 cells. Therefore, Tregs inhibited the expression of COX-2 in vulnerable plaques and macrophages, and COX-2 inhibition may be an important effect of Tregs that results in atherosclerotic plaque stabilization.