Feeding a diet rich in eicosapentaenoic acid (EPA) to Watanabe heritable hyperlipidemic (WHHL) rabbits resulted in an attenuated aortic contractile response to the vasoconstrictor agent serotonin when compared to responses from WHHL rabbits fed normal rabbit chow. In contrast, only the maximal contractile response to norepinephrine was reduced in EPA-fed rabbit aortas. Additionally, methacholine-induced relaxations were potentiated in aortas obtained from the EPA-fed rabbits. When platelets obtained from EPA-fed rabbits were incubated with arachidonic acid, there was a reduced ability of the platelets to adhere to albumin-coated discs in comparison to control rabbit platelets. These data indicate a potentially beneficial effect of EPA in atherosclerotic WHHL rabbits.