Background: LCn-3PUFA comprised of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) offer cardioprotection involving a decrease in coagulant activity; however, the evidence is equivocal. We have previously demonstrated that the acute (24 h) effects and chronic (4 weeks) effects of LCn-3PUFA supplementation on platelet aggregation in human subjects are sex specific. This study investigated the mechanisms of the sex-dependent effects of LCn-3PUFA with 4 weeks supplementation of EPA-rich vs. DHA-rich oils on procoagulant and platelet activity in healthy subjects. Design: A double-blinded, placebo-controlled randomised trial was conducted in 94 healthy adults: male (n=41) and female (n=53). Platelet coagulation parameters including factors I, II, V, VII, VIII, IX, X, vWF:Ag and endogenous thrombin potential were measured at baseline and 4 weeks postsupplementation with EPA-rich or DHA-rich oil capsules. Results: We have previously reported that platelet aggregation is specifically reduced by supplementation with EPA in males and DHA in females. This sexspecific effect was also observed for decreases in plasma levels of Factor II (-7.9 +/- 3.8%, P=.026), Factor V (-6.5 +/- 4.5%, P=.022) and vWF:Ag (-7.3 +/- 2.1%. P=.034) and was most pronounced in males supplemented with EPA. In contrast, DHA-mediated reduction in platelet aggregation in females was not accompanied by any significant changes in the coagulation parameters tested. Conclusion: Significant interactions between sex and specific LCn-3PUFA exist to reduce procoagulant activity differentially in males vs. females and could have profound effects on managing risk of thrombotic disease. (C) 2014 Elsevier Inc. All rights reserved.