Twenty hypertensive subjects participated in three clinical trials of 13 days each, to examine the effects of Alsepa fish oil (20:5, n-3 eicosapentaenoic acid (EPA) 180 mg, and 22:6 n-3 docosahexaenoic acid (DHA) 120 mg) on n-3 for n-6 polyunsaturated fatty acids (PUFA) exchange on serum phospholipids, blood pressure (BP), triglycerides (TG) and primary hemostasis. After 13 days, plasma phospholipids showed an increase in Sigman-3 (EPA and DHA) from 2.0 to 5.9% (P < 0.01), and a decrease in Sigman-6 (arachidonic acid and linoleic acid) from 29.8 to 22.6% (P < 0.01). A concomitantly significant reduction in systolic BP (SBP) (158.7 plus or minus 23.8 mmHg to 146.5 plus or minus 17.0 mmHg, P = 0.04), and diastolic BP (DBP) (80.8 plus or minus 8.4 mmHg to 72.9 plus or minus 14.9 mmHg, P = 0.04) as well as a significant decrease in platelet adhesion and aggregation on extra cellular matrix measured as a percentage of surface coverage (11.9 plus or minus 4.8% to 4.2 plus or minus 3.2%, P = 0.0001) was observed. In addition, a significant reduction in baseline dependent To was observed; the higher the baseline level TG, the more pronounced the reduction (average 159.2 plus or minus 74.6 mg% to 108.0 plus or minus 46.1 mg%, P = 0.001). No change was observed in total cholesterol, high and low density lipoprotein (HDL, LDL), platelet and fibrinogen. Repeated fasting and refeeding with fish oil facilitated plasma exchange of n-3 for n-6 PUFA, improved BP, clinical metabolic parameters and lowered platelet reactivity in the vessel wall (primary hemostasis). In severe and life-threatening situations, the beneficial effects of fish oil should be considered for rapid exchange of n-3 for n-6 PUFA. In this study we describe a novel approach for rapid fatty acid exchange by fasting/refeeding with fish oil supplementation, as well as improved BP, plasma lipids and primary hemostasis. Further research is required on the therapeutic use of fish oils and the physiological mechanisms involved in fatty acid exchange.