Animal studies suggest that the 2 major omega3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (P<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (P=0. 001). Relative to the placebo group, DHA reduced 24-hour HR by 3. 5+/-0.8 bpm, daytime HR by 3.7+/-1.2 bpm, and nighttime HR by 2. 8+/-1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1. 66+/-0.07% to 9.83+/-0.06% (P<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00+/-0.27% to 10.93+/-0.62% (P<0.0001) and led to a small, nonsignificant increase in EPA (1.52+/-0.12% to 2.26+/-0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal omega3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry.