Epidemiological studies have suggested an association between consumption of red wine and other polyphenolic compounds and prevention of cardiovascular diseases. In the present study, Watanabe heritable hyperlipidemic (WHHL) rabbits were used to investigate the effects of polyphenols in a red grape skin and seed extract (GSE) on the development of atherosclerosis. WHHL rabbits received either semisynthetic diet (casein based) or semisynthetic diet added GSE over a period of 15 wk. Plasma lipids and aortic cholesterol accumulation were measured. Feeding semisynthetic diet was associated with increasing hypercholesterolemia, which was developing slower in GSE group compared to the controls as recorded by significantly lower plasma cholesterol in dosage week 7 (males: P < 0.05, females: P < 0.01) and 11 (males: P < 0.01). Aortic atherosclerosis evaluated as the cholesterol content in aortic tissue was comparable in the control and GSE-dosed females, but it was significantly reduced in the abdominal part of GSE-dosed male compared to the controls (P < 0.05). In conclusion, feeding GSE extract to WHHL rabbits had no significant effects in females but was associated with transient less hypercholesterolemic response to semisynthetic diet and, furthermore, retarded the development of aortic atherosclerosis in males as demonstrated by significantly lower cholesterol content in the abdominal part.