Omega-3 (ω3) fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular disease. Despite these benefits, concern remains that ω3 fatty acids may increase lipid peroxidation. It has previously been shown that urinary F2- isoprostanes (F2-IsoPs) were reduced following ω3 fatty acid supplementation in humans. It is now determined whether EPA or DHA supplementation affects plasma F2-IsoPs. In two 6-week placebo-controlled interventions, Study A: overweight, dyslipidaemic men; and Study B: treated-hypertensive Type 2 diabetic, patients were randomized to 4 g daily EPA, DHA. Post-intervention plasma F2-IsoPs were significantly reduced by EPA (24% in Study A, 19% in Study B) and by DHA (14% in Study A, 23% in Study B) relative to the olive oil group. The fall in plasma F 2-IsoPs was not altered in analyses that corrected for changes in plasma arachidonic acid, which was reduced with EPA and DHA supplementation. Neither F3-nor F4-IsoPs were observed in plasma in both studies. These results show that in humans, EPA and DHA reduce in vivo oxidant stress as measured in human plasma and urine.