In 36 normolipemic pigs randomized to a 4-week feeding with regular pig chow (n=18, control group) or chow supplemented with cod liver oil (1 ml/kg per day) (n=18, treated group), treatment with cod liver oil produced a significant decrease in serum cholesterol, low density lipoprotein cholesterol, and triglycerides. Deep carotid arterial wall injury (media exposed) by balloon angioplasty was associated with less111In-labeled platelet deposition (24.6±4.8×106/cm2versus 62.5±17.0×106/cm2, p<0.05; difference, −33.8×106/cm2; 95% confidence interval [CI], −1.9×106/cm2to −73.9×106/cm2) and injury-related vasoconstriction (21.3±2.2% versus 30.9±2.9o,p<0.05; difference, −9.6%; 95% CI, −2.2% to −17.00) in the cod liver oil-treated group than in the control group; with mild injury (media not exposed), platelet deposition was low and unchanged (6.2±0.5×106/cm2versus 7.8±0.7×106/cm2; difference, −1.6×106/ cm2; 95% CI, −1.1×106/cm2to +4.3×106/cm2), but associated vasoconstriction was reduced respectively (16.3±2.0% versus 23.0±2.2%,p<0.05; difference, −6.7%; 95% CI, −0.6% to −12.8%). When arterial blood from cod liver oil-treated pigs superfused normal aortic media ex vivo, platelet deposition onto the normal aortic media was lower than when arterial blood from control pigs superfused the normal aortic media (43.7±8.8×106/cm2versus 66.8±13.0×106/cm2,p<0.05). A mild increase in the eicosapentaenoic acid/arachidonic acid ratio to 0.5 or greater was associated with a significant reduction in platelet deposition and vasoconstriction, whereas a ratio in excess of 2.0 was needed to significantly lower serum lipid levels. In addition, there were no correlations between serum cholesterol and platelet deposition or vasoconstriction, making it unlikely that the modest reduction in serum lipids would influence the acute platelet-arterial wall interactions. These beneficial effects of cod liver oil on platelet-arterial wall interactions, occurring with only a mild increase in the eicosapentaenoic acid/arachidonic acid ratio, may have implications for thrombosis and vasospasm after deep arterial injury.