The effects of ethyl all-cis-5,8,11,14,17-icosapentaenoate (EPA-E), highly purified ethyl ester of icosapentaenoic acid (EPA), on rabbit platelets were studied. In in vitro, highly purified EPA (62.5-3000 microM) suppressed the platelet aggregation induced by collagen, arachidonic acid (AA) and adenosine diphosphate (ADP). In ex vivo, a single administration of EPA-E (300 and 1000 mg/kg, p.o.) and repeated administrations (30 and 300 mg/kg/d, p.o.) for 2 weeks showed no effects on collagen-, AA- and ADP-induced platelet aggregation. Repeated administrations (30 and 300 mg/kg/d, p.o.) for 4 weeks suppressed the collagen-induced platelet aggregation, but not the AA- and ADP-induced platelet aggregation. Repeated administrations for 4 weeks also suppressed thromboxane B2 (TXB2) formation induced by collagen, but a single administration and repeated administrations for 2 weeks failed to inhibit TXB2 formation. The EPA level in the platelet phospholipids increased slightly with a single administration, and increased markedly with repeated administrations for 2 and 4 weeks. The AA level in the phospholipids showed practically no changes with a single and repeated administrations. These results suggested that highly purified EPA-E could reduce platelet aggregability by the change of the EPA level in the platelet phospholipids and should allow for a reasonable period of administration.