Diets rich in eicosapentaenoic acid [EPA; 20:5(n-3)] are associated with decreased arterial stiffness, but postprandial effects on vascular function are unknown. We investigated whether an EPA-enriched high-fat meal could improve postprandial vascular function. Seventeen healthy men ingested 2 test meals (51 g fat), 1 wk apart, in random order: 5 g EPA plus high-oleic sunflower oil (HOS) vs. HOS only. A second high-fat meal (44 g fat), the same on both study days, was provided 4 h later. Blood pressure and arterial function were measured using digital volume pulse (DVP) to derive a stiffness index (DVP-SI) and reflection index in fasting subjects at 3 and 6 h following the test meal. Blood samples were taken following the test meal for plasma 8-isoprostane F2alpha, nitric oxide (NO) metabolites (NOx), glucose, insulin, triacylglycerol, and fatty acid analysis. The plasma EPA concentration (mean +/- SD) reached a peak of 2.10 +/- 0.99 mmol/L following the EPA meal (5 h) and did not rise above 0.27 +/- 0.16 mmol/L 1 h following the placebo meal. DeltaDVP-SI did not differ between the 2 test meals at 3 h but was greater at 6 h following EPA (6 h -0.65 +/- 0.65 m/s) compared with placebo (6 h -0.33 +/- 1.26 m/s). Plasma 8-isoprostane F2alpha concentrations increased by 48% at 6 h compared with baseline following the EPA meal and plasma NOx decreased following both meals, with no differences between the meals in the changes. Changes in other variables measured also did not differ after subjects consumed the 2 meals. In conclusion, adding EPA to a high-fat meal results in acute changes in vascular tone, independent of changes in oxidative stress.