Type 2 diabetes is considered a "risk equivalent" for cardiovascular disease, rosiglitazone, as an insulin sensitizer, has been explored as a novel therapeutic drug for the prevention of cardiovascular disease, but whether it can stabilize vulnerable atherosclerotic plaques is still unknown. Our study aims to investigate the effect of rosiglitazone on plaque stability in fat-fed ApoE-knockout mice. Our findings showed that rosiglitazone can stabilize the vulnerable atherosclerotic plaques in fat-fed ApoE-knockout mice by modifying the plaque composition as well as decreasing the number of buried fibrous caps and its anti-inflammatory effect probably is the key mechanism through which promotes the plaque more stable.