Background: The Reduction of Cardiovascular Events with Icosapent Ethyl (IE)–Intervention Trial (REDUCE-IT) showed that patients with elevated baseline triglyceride and well controlled LDL-C levels on statins had a 30% lower risk of first and recurrent ischemic events, including cardiovascular death, in those who received 2 g of IE twice daily compared to placebo. In this study, we conducted scenario analyses of lifetime cost-effectiveness (CE) of IE compared with standard care (SC) alone. Methods: We applied treatment effects from REDUCE-IT, health care costs from national sources, and costs for IE of $4.16 a day and conducted a combination CE analysis utilizing patient level in-trial cost and clinical outcomes and long-term costs, events, and life expectancy derived from Markov simulation models. The model projected lifetime health care costs, cardiovascular events, survival, and quality-adjusted life-years (QALYs) for IE versus SC in eligible patients from a payer perspective. Scenario analyses included lifetime extension of in-trial base case and other four cases. In the lifetime base case, IE adherence and treatment effects would be assumed to reduce linearly beginning after the trial period and extending to 20 years post baseline. In the best case, patients in the IE group would adhere to treatment persisting for the rest of their lives. In the worst case, patients in the treatment group would stop adhering to IE immediately after the trial period. In the fourth scenario, patients would continue to take treatment drug but the effect of the drug would decrease effectiveness over 15 years. In the fifth scenario, patients in the treatment group would have disutility from taking IE. Results: The QALYs for IE and SC were 3.34 and 3.27 in-trial and 11.61 and 11.35 lifetime, respectively. Without background cost, the mean costs for IE and SC in-trial were $23,926 and $24,563 and lifetime $87,077 and $88,912, respectively. IE was a dominant strategy, in-trial 73.2% and lifetime 71.6% of simulations. In probabilistic sensitivity analysis, 91.9% of simulations indicated that IE would be cost-effective (i.e., below $50,000 per QALY gained). In the lifetime base case, the probability of CE at the $50,000, $100,000, and $150,000 threshold was 91.6%, 92.6%, and 93.2% of simulations, respectively. In the best case, the probability that IE was cost-effective was 98.4%, 99.0%, and 99.3% at the $50,000, $100,000, and $150,000 per QALY gained thresholds, respectively. In the worst case scenario, the probability that IE was cost-effective was 88.1%, 89.4%, and 90.5% at the $50,000, $100,000, and $150,000 per QALY gained , respectively. Similar results were shown in the fourth and fifth scenarios. Conclusions: Icosapent ethyl at a cost of $4.16/day was shown to be cost-effective at willingness-to-pay thresholds of $50,000 per QALY, and a dominant strategy in all post trial persistence-of-IE-effect scenarios.