Reinioside C is a triterpene saponin from the the root of Polygala aureocauda Dunn (PAD). This study examined the effects of reinioside C on hyperlipidemic mice in vivo and endothelium cells, macrophages and smooth muscle cells in vitro. Mice were given a hyperlipidemic diet for 30 days, then administered reinioside C (4, 8, 16 mg/kg/day, p.o.) for 30 days. Then the serum lipid, superoxide dismutase (SOD), malonaldehyde (MDA), the total cholesterol (TC) and triglyceride (TG) in the liver extract were measured. Human umbilical vein endothelial (HUVECs), peritoneal macrophages and smooth muscle cells (SMCs) pre‐treated with reinioside C were treated with oxidized low‐density lipoprotein (OxLDL). The results showed that reinioside C decreased serum and liver tissue lipid profiles in hyperlipidemic mice. Moreover, reinioside C protected the HUVECs against the Ox‐LDL induced LDH leakage and exerted a protective effect on oxidative lesions induced by OxLDL, inhibited cholesteryl ester accumulation in macrophages, and decreased [Ca²⁺]_i and SMC proliferation in vitro. Based on these results, it is suggested that reinioside C is a promising hypolipidemic candidate. Copyright © 2007 John Wiley & Sons, Ltd.