AIM To evaluate lipid-lowering efficacy and safety of RYR Cholestin, or Monascus purpureus (Red Yeast) Rice, in American subjects with moderate hypercholesterolemia. METHODS This study was an open-label, self-pairing design, multi-center clinical trial. A total of 187 subjects were entered into this trial (serum LDL-cholesterol 3.50～4.92 mmol﹒L-1; Total cholesterol 5.18～7.25 mmol﹒L-1; male:female=116:71), of which 162 completed the study. Subjects were placed on the NCEP Step I Diet throughout the study and RYR Cholestin (2.4 g﹒day-1) for 8 wk following initial 4-wk diet control. RESULTS Maintenance on the diet alone for 4 wk resulted in no significant changes in serum lipids. RYR Cholestin treatment for 8 wk reduced serum total cholesterol, LDL-cholesterol and triglycerides by 16.6%, 24.0%, and 25.2%, respectively; and increased HDL-cholesterol by 14.3% (all P<0.001). There were 98% of patients having a ≥10% improvement in at least one of lipid risk factors, and 79% having a ≥20% improvement. Discontinuation of RYR Cholestin intervention for 14 d led to a return of serum lipids to baseline of pre-study. 29 possible product-related adverse reactions were reported and all adverse reactions were mild. CONCLUSION RYR Cholestin was well tolerated and was effective in reducing total and LDL-cholesterol, and triglycerides, as well as in increasing HDL-cholesterol in hypercholesterolemic patients, but those items return to the beginning baseline when the treatment discontinued.