Efficacy of a new patented proprietary combination of natural nutraceuticals (PN) containing natural hypolipidemic as red yeast, policosanol and berberine was tested in a large study on dyslipidemic patients in clinical practice. A parallel, controlled, randomized, multicenter study was designed. After 2 weeks on a stable dietary regimen, the patients were randomized to PN 1 tablet/day associated with diet (PN + D) or diet alone (D) for 16 weeks. Entry criteria were: Tot-Chol >200 mg/dL or LDL-Chol >150 mg/dL without a clear indication for statins, or plasma triglycerides >150 mg/dL. Lipid pattern and CV parameters were evaluated at baseline and monthly. 1,751 patients were enrolled in 248 Italian units, 933 patients on PN + D and 818 on D. The baseline lipid values were: Tot-Chol 255.4 versus 243.1 mg/dL, LDL-Chol 170.1 versus 162.2 mg/dL, HDL-Chol 50.0 versus 48.8 mg/dL, and TG 190.5 versus 184.4 mg/dL. PN constantly and significantly improved lipid parameters versus D group: at 16 weeks −19.1 versus −9.4% for Tot-Chol (p < 0.001), −23.5 versus −10.8% for LDL-Chol (p < 0.001), +11.6 versus +4.0% for HDL-Chol (p < 0.001), −17.9 versus −11.3% for TG (p < 0.001). In conclusions, PN plus diet allows an effective improvement of blood lipids with a significant reduction of global CV risk, suggesting a role for PN in CHD prevention.