Tanshinone II A (TSIIA) is a diterpene quinone extracted from the roots of Salvia miltiorrhiza with anti-inflammatory and anti-oxidant properties that is used to treat atherosclerosis. In the current study, morphological analyses were conducted to evaluate the effects of TSIIA on atherosclerotic vulnerable plaque stability. Additionally, receptor of advanced glycation end products (RAGE), adhesion molecule, and matrix-metalloproteinases (MMPs) expression, and nuclear factor-kappa B (NF-kappa B) activation were examined in apolipoprotein E (apoE)-deficient mice treated with TSIIA. Eight-week-old apoE(-/-) mice were administered TSIIA and fed an atherogenic diet for 8 weeks. TSIIA exhibited no effects on plaque size. Analysis of the vulnerable plaque composition demonstrated decreased numbers of macrophages and smooth muscle cells, and increased collagen content in apoE-deficient mice treated with TSIIA compared with untreated mice. Western blotting revealed that TSIIA downregulated the expression levels of vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and MMP-2,-3, and-9, suppressed RAGE, and inhibited NF-kappa B, JNK and p38 activation. The present study demonstrated that the underlying mechanism of TSIIA stabilization of vulnerable plaques involves interfering with RAGE and NF-kappa B activation, and downregulation of downstream inflammatory factors, including ICAM-1, VCAM-1, and MMP-2,-3 and-9 in apoE(-/-) mice.