The effect of fish oil administration on platelet function was studied in eight normal individuals, four men and four women, who received fish oil equivalent to 6 g eicosapentaenoic acid per day for a period of 25 days. Platelet aggregation, platelet adhesion, phospholipid and fatty acid distribution were measured at periodic intervals before, during, and after the period of fish oil administration. Platelet aggregation induced by arachidonic acid, adenosine diphosphate, and collagen showed a moderate increase in ED 50 in response to the administration of fish oil. Conversely, platelet adhesion to fibrinogen and collagen I, which was studied at low shear rates in a laminar flow chamber, showed a striking 60% to 65% decrease after fish oil supplementation of the diet. The change in adhesiveness could be correlated with the pseudopodia formed in response to agonistic stimulation. Scanning electron microscopic examination of adherent platelets showed an overall reduction of pseudopodia that appeared short and stubby on fish oil administration. The profile of the fatty acids extracted from plasma confirmed compliance of the volunteers with their dietary supplements. Analysis of phospholipids showed changes in sphingomyelin, lysophosphatidylcholine, and phosphatidylcholine between pseudopodia and platelet cell bodies. Fish oil administration did not affect their overall distribution except for a moderate decrease in phosphatidylethanolamine in platelet pseudopodia. Changes were also recognized in the total fatty acids extracted from platelets, affecting primarily arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. There were no changes in platelet adhesiveness in a group of five normal individuals who received a vegetable oil supplement of equal dose and duration as that of the fish oil. We conclude from these studies that fish oil, at least when administered over a limited period of time, is an effective inhibitor of platelet adhesiveness.