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We evaluated the effects of <i>Cynanchum wilfordii</i> (CW) ethanolic extract on blood cholesterol levels in adults with high low-density lipoprotein cholesterol (LDL-C) levels. In a double-blind, randomized, placebo-controlled, parallel trial, 84 subjects were recruited. Participants were randomly divided into two groups with a low-dose (300 mg/d) or high-dose (600 mg/d) of CW. Levels of very low-density lipoprotein (<i>p</i> = 0.022) and triglycerides (<i>p</i> = 0.022) were significantly lower in the low-dose CW group than in the placebo group after 8 weeks. In a subgroup of participants with LDL-C&#8805; 150 mg/dL (<i>n</i> = 33), there was a significant decrease in total cholesterol (low-dose, <i>p</i> = 0.012; high-dose, <i>p</i> = 0.021), apolipoprotein B (low-dose, <i>p</i> = 0.022; high-dose, <i>p</i> = 0.016), and cholesteryl ester transfer protein (low-dose, <i>p</i> = 0.037; high-dose, <i>p</i> = 0.016) after 8 weeks of CW. The correlation between changes in total cholesterol and baseline LDL-C levels was significant in the groups that received both doses of CW (low-dose, <i>p</i> = 0.010; high-dose, <i>p</i> = 0.015). These results show that the CW ethanolic extract can regulate blood cholesterol in subjects with LDL-C&#8805; 150 mg/dL.