Abstract Background and Objective Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid (EPA) ethyl ester approved to reduce triglyceride levels in patients with severe (C5.65 mmol/L) hypertriglyceridemia. EPA, the active metabolite of IPE, is mainly metabolized via b-oxidation, and studies suggest that omega-3 fatty acids such as EPA may have antithrombotic effects. The objective of this study was to evaluate the effect of IPE on the pharmacokinetic and anticoagulation pharmacodynamics of warfarin, a substrate of cytochrome P450 2C9-mediated metabolism. Methods Healthy adults received oral warfarin (25 mg) on day 1, oral IPE (4 g/day) on days 8-35, and coadministration on Day 29. Primary pharmacokinetic end points were area under the concentration-versus-time curve from zero to infinity (AUC 0-? ) and maximum plasma concentration (C max ) for R-and S-warfarin; pharmacodynamic end points were area under the international normalized ratio (INR) effect-time curve after the warfarin dose (AUC INR ) and maximum INR (INR max ). Results Twenty-five subjects completed the study. AUC 0-? and C max ratios of geometric means for both Rand S-warfarin following co-administration of warfarin with versus without IPE were within the 90 % confidence intervals of 0.80-1.25. AUC INR , INR max , and ratios were also similar. Conclusions IPE 4 g/day did not significantly change the single-dose AUC 0-? or C max of R-and S-warfarin or the anticoagulation pharmacodynamics of warfarin when coadministered as racemic warfarin at 25 mg. Co-administration of these drugs was safe and well tolerated in this study of healthy adult subjects. Key Points Patients who are candidates for icosapent ethyl therapy may also be receiving warfarin anticoagulation therapy. Icosapent ethyl 4 g/day did not have an effect on the pharmacokinetics or anticoagulation pharmacodynamics of warfarin. Co-administration of icosapent ethyl and warfarin was safe and well tolerated