Background: Atherosclerosis is closely associated with proliferation of the adventitial vasa vasorum, leading to the atherosclerotic plaque progression and vulnerability. In this report, we investigated the role of Ginsenoside Rb-1 (Rb-1) on atherosclerotic plaque stabilization and adventitial vasa vasorum (VV) along with the mechanisms involved. Methods and Results: Apolipoprotein E-deficient (ApoE(-/-)) mice were fed with a high-fat diet for 20 weeks, and then Ginsenoside Rb-1 (50 mg/kg/d, intraperitoneal) was given for 4 weeks. Rb-1 treatment significantly inhibited adventitial VV proliferation, alleviated inflammation, decreased plaque burden, and stabilized atherosclerotic plaques in apoE(-/-) mice. However, the beneficial effects of Rb-1 on atherosclerotic lesion was attenuated by overexpression of miR-33. The analysis from atherosclerotic plaque revealed that Rb-1 treatment could result in an induction of Pigment epithelium-derived factor (PEDF) expression and reduction of the miR-33 generation. Overexpression of miR-33 significantly reverted the Rb-1-mediated elevation of PEDF and anti-angiogenic effect. Conclusions: Ginsenoside Rb-1 attenuates plaque growth and enhances plaque stability partially through inhibiting adventitial vasa vasorum proliferation and inflammation in apoE(-/-) mice. The anti-angiogenic and anti-inflammation effects of Rb-1 are exerted via the modulation of miR-33 and its target gene PEDF.