We compared the cardiovascular risk-reduction potential of three major polyunsaturated fatty acids in a double-blind study. Thirty-three normotensive and mildly hypercholesterolemic men were randomly allocated to one of three diets supplemented with linoleic acid (14.3 g/d), alpha-linolenic acid (9.2 g/d), or eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) (3.4 g/d). Diets were matched to provide similar amounts of the major classes of fatty acids and cholesterol. Blood pressure and plasma lipids were measured for 6 wk after a 3-wk run-in period on the linoleic acid supplement. For the diet supplemented with EPA plus DHA compared with the linoleic acid diet systolic blood pressure fell 5.1 mm Hg (p = 0.01); plasma triglyceride and VLDL cholesterol fell by 39% (p = 0.001) and 49% (p = 0.01), respectively; and LDL cholesterol rose by 9% (p = 0.01). There were no significant changes with the diet supplemented with alpha-linolenic acid. The net effect on cardiovascular risk therefore is complex and the systolic blood pressure reduction was substantial.