Epidemiological studies have produced solid evidence that consumption of fruits results in a reduction of cancer and cardiovascular disease. Red wine has been hypothesized to reduce the risk of heart disease as a result of its antioxidant, endothelial relaxation, and antiplatelet aggregation mechanisms. We investigated a commercial California wine grapeseed extract, MegaNatural((R)) Gold, and compared it to grapes, grape juice, red wine, other grapeseed extracts, and commercial extracts with respect to antioxidant activity, using an oxidation-reduction colorimetric assay. The quality of the antioxidants was determined with the use of an in vitro model of heart disease, a dose-response inhibition of low-density lipoprotein oxidation. MegaNatural((R)) Gold had a superior quantity/quality antioxidant index compared with all other samples tested. In nine subjects given 600 mg of MegaNatural((R)) Gold, the plasma antioxidant activity as measured by the RANDOX assay was significantly increased by 12% after both 1 and 2 hours. This was equivalent to drinking 300 ml of red wine or consuming 1,250 mg of vitamin C, as found in a previous study. We then determined the dose-response human plasma bioavailability of one of the polyphenols in MegaNatural((R)) Gold (epicatechin) in nine human subjects after giving 200 and 300 mg of the product. The in vivo antioxidant activity was also measured. The higher dose was much more effective. A long-term human supplementation study with 2 x 300 mg/day of MegaNatural((R)) Gold was then done on 17 (9 normal and 8 hypercholesterolemic) subjects. Plasma cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations were significantly decreased in the subjects with high cholesterol. Triglycerides were significantly increased in the high-cholesterol subjects but were still in the normal range after supplementation. Plasma antioxidant capacity was significantly improved in the high-cholesterol subjects. There was no change in plasma lipids or antioxidant capacity in the normal subjects.