Background: Patients with end-stage renal disease on hemodialysis have excess cardiovascular disease (CVD) burden with substantially increased CV event rates compared with the general population. Summary: Traditional interventions that, according to standard clinical guidelines, reduce CV risk such as antihypertensive therapy, diet, exercise, and statins are not similarly effective in the hemodialysis population. This raises the question of whether additional risk factors, such as enhanced inflammation and oxidative stress, may drive the increased CVD burden in hemodialysis patients. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into the atherosclerotic plaque as well as membrane phospholipid bilayers and produces beneficial effects on inflammatory and oxidative mechanisms involved in atherosclerotic plaque formation and progression. EPA levels and the ratio of EPA to the omega-6 polyunsaturated fatty acid arachidonic acid (AA) are reduced in hemodialysis patients. Serum EPA levels have been inversely correlated with proinflammatory cytokines, and the EPA/AA ratio has been inversely associated with CV events in hemodialysis cohorts. Three recent studies involving over 800 hemodialysis patients and follow-up of 2-3 years suggest that EPA therapy may improve clinical outcomes in this patient population as evidenced by significant reductions in cardiovascular mortality, all-cause mortality, and/or CV events. Key Messages: Further studies with high-purity EPA are warranted in patients on hemodialysis, especially given the fact that other interventions including antihypertensives, diet, exercise, and statins have not provided meaningful benefit.