Cardiovascular outcome trials on omega-3 fatty acids have generated contradictory results but indicate a dose-dependent beneficial effect of eicosapentaenoic acid (EPA). Beneficial cardiovascular effects of EPA may in addition to triglyceride lowering be mediated through alternative mechanisms of action. In this review, the link between EPA and a resolution of atherosclerotic inflammation is addressed. EPA is a substrate for the enzymatic metabolism into the lipid mediator resolvin E1 (RvE1), which activates the receptor ChemR23 to transduce an active resolution of inflammation. This has been shown to dampen the immune response and provide atheroprotective responses in different models. The intermediate EPA metabolite 18-HEPE emerges as a biomarker of EPA metabolism towards proresolving mediators in observational studies. Genetic variations within the EPA-RvE1-ChemR23 axis affecting the response to EPA may open up for precision medicine to identify responders and non-responders to EPA and fish oil supplementation. In conclusion, activation of the EPA-RvE1-ChemR23 axis towards a resolution of inflammation may contribute to beneficial effects in cardiovascular prevention.