The effect of dietary supplementation with fish oil was investigated in the Watanabe heritable hyperlipidemic (WHHL) rabbit. Rabbits were fed Maxepa (1 g/kg body weight) from weaning for a 6-month period and were compared to controls. Fish oil supplements resulted in significant decreases in plasma triglyceride and cholesterol at 4 weeks after the start of the study, and these differences persisted over the 6-month period. No differences in the distribution of cholesterol or triglyceride among lipoprotein particles were found, nor were there differences in low density lipoprotein particle size. The decreases in plasma cholesterol and triglyceride were accompanied by significant increases in the percent of eicosapentaenoic and docosahexaenoic acids in both plasma and platelets. Fish oil supplementation resulted in a decrease in platelet count and response to the aggregating agents adenosine diphosphate, arachidonic acid, and collagen. Systolic blood pressure was significantly lower in the rabbits fed fish oil. At the end of the study period, aortic free and esterified cholesterol and intimal surface area covered with plaque were determined in the arch and in the descending and abdominal aorta. Significantly less cholesterol was found in the descending and abdominal aorta. These differences were mirrored by decreased activities of acid lipase and N-acetyl-beta-glucosaminidase. In contrast, no differences in the intimal surface area covered with plaque were found. In conclusion, dietary fish oil resulted in a decrease in aortic lipid deposition in the WHHL rabbit, which may have been due to decreases in plasma triglyceride and cholesterol, platelet count and aggregability, and systolic blood pressure.