Sprague-Dawley rats fed a diet containing 12% fish oil (18% eicosapentaenoic acid [EPA] and 12% docosahexaenoic acid [DHA]), for 1 week (group I, n = 9) or 8 weeks (group III, n = 42) and controls (group II, n = 8; group IV, n = 36, respectively) were subjected to 35 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion. Compared to the controls, infarct size was significantly reduced in group III (15% +/- 2%, n = 42 vs 34% +/- 4%, n = 36; p < 0.001; infarct mass/risk area x 100%), but no change in group I (39% +/- 5%, n = 9 vs 35% +/- 5%, n = 8; p = not significant). Bleeding time was prolonged in group III (290 +/- 73 sec) compared to group IV (99 +/- 10 sec, p = 0.015). Omega-3 fatty acid (EPA and DHA) levels in platelets were significantly higher in the rats fed 8 weeks of fish oil (group III) compared to the controls (group IV) and the rats fed 8 weeks of fish oil and then a regular diet until bleeding time normalized (group V) (7.2% +/- 0.6% vs 1.2% +/- 0.2% and 4.9% +/- 0.5%; 3.8% +/- 0.7% vs 1.8% +/- 0.3% and 2.8% +/- 0.6%, p < 0.001 and 0.05, respectively). These data indicate that long-term (8 weeks) dietary fish oil supplementation significantly reduces infarct size; short-term (1 week) does not. This reduction of infarct size appears to correlate with altered platelet function and EPA and DHA levels in platelets.