There is evidence to indicate that the high rates of coronary heart disease and myocardial infarction amongst Indians of Asian descent may be partly related to circulating nonesterified fatty acids (NEFA). As docosahexaenoic acid (DHA,22:6n-3) in NEFA form has been found to exhibit anti-platelet aggregatory and anti-arrhythmic potential in vitro, the effect of supplementary DHA was examined in healthy subjects of Asian Indian background. Furthermore, time- and dose-dependent changes in absolute levels of DHA as NEFA or phospholipid (PL) were compared. The subjects consumed 8 capsules daily of placebo (DHA-free) or low DHA (0.75 g/day)or high DHA (1.50 g/day) over 6 wks. Fasting blood samples were drawn at days 0, 21, and 42 for analysis of serum lipid/lipoprotein composition. No significant effect of DHA supplementation on the levels of serum lipid/lipoproteins (including Lp[a]) or blood pressure was found. However, the DHA level in serum phospholipid rose by 167% overall with low-dose supplementation (from 2.4-6.4 mol%) but only by an additional 23% upon doubling the dose from 0.75 g to 1.50 g/day. Furthermore, after 6 weeks of supplementation with 0.75 g or 1.5 g DHA/day, absolute concentrations of DHA as PL were not significantly different from the corresponding 3-week values. Interestingly, the absolute concentrations of serum DHA as NEFA showed a marked rise with low-dose supplementation (by 212% overall, from 2.4 to 7.5 microM) and a further 70% rise (to 12.7 microM) upon doubling the supplementation from 0.75 to 1.50 g/day. As well, the 6-week concentrations (DHA-NEFA) were significantly different than the corresponding 3-week values at both dose levels. Elevation of circulating DHA-NEFA levels via DHA supplementation, as shown herein, to concentrations that exhibit anti-thrombotic and anti-arrhythmic potential in vitro needs to be extended to trials where clinical end-points are determined.