There is disagreement about whether supplementation of the diet with fish oil, which is rich in eicosapentaenoic acid (EPA), lowers blood pressure. We gave highly purified EPA in a soft capsule (90% ethyl ester form of EPA; EPA-E), to female rabbits (100 mg/kg/day) for 4 weeks. Vascular response to vasoconstrictor agents was assessed serially by measuring the systolic blood pressure using a Grand-Rothschild capsule in the ear. There was no change in systolic blood pressure of rabbits treated with EPA-E, but rabbits given EPA-E for one week or longer were significantly less responsive to the pressor effects of angiotensin II than the controls. Responses to norepinephrine did not change. Rabbits given EPA-E for four weeks had significantly more EPA in the serum, but there were no differences in serum levels of triglycerides, total cholesterol, or high-density lipoprotein cholesterol. These results suggest that vascular responses to exogenous angiotensin II can be selectively depressed by short-term treatment with EPA-E in rabbits without changing systolic blood pressure.