This study was designed to clarify the effects of orally administered eicosapentaenoic acid (EPA) on blood pressure, intracellular sodium content, and cell membrane fatty acid composition in patients with essential hypertension. After a 4-week run-in period, a study group of 17 male patients was assigned to an 8-week treatment with EPA (2.7 g/day) or placebo in a randomized, double-blind fashion with a crossover at week 4. Systolic blood pressure (SBP) was lower after treatment with EPA than after treatment with placebo (152.9+/-17.3 vs. 162.6+/-20.6 mmHg; p<0.01), while diastolic blood pressure was not statistically different. Compared with the placebo treatment, EPA supplementation resulted in a decrease in intraerythrocyte sodium content (R-Na; 11.17+/-0.63 vs. 10.44+/-1.28 nmol/l cells; p<0.05) accompanied by an increase (p<0.001) in erythrocyte membrane EPA content. The increase in membrane EPA content was related to the decrease in SBP (r=-0.52, p<0.05) and the decrease in R-Na (r=-0.57, p<0.02) during EPA treatment. The decrease in R-Na correlated positively with the decrease in SBP (r=0.54, p<0.05), and correlated negatively with the change in Na+-K+ ATPase activity (r= -0.59, p<0.02). However, the change in Na+-K+ ATPase activity did not directly correlate with the change in membrane EPA content. In conclusion, oral EPA supplementation increased membrane EPA content and reduced SBP in patients with essential hypertension. Based on the association between the increase in membrane EPA content and the decrease in intracellular sodium concentration, EPA may lower blood pressure by altering the activities of the membrane sodium transport systems.