Background In 3146 REDUCE‐IT USA (Reduction of Cardiovascular Events With Icosapent Ethyl Intervention Trial USA) participants, icosapent ethyl (IPE) reduced first and total cardiovascular events by 31% and 36%, respectively, over 4.9 years of follow‐up. Methods and Results We used participant‐level data from REDUCE‐IT USA, 2021 US costs, and IPE costs ranging from $4.59 to $11.48 per day, allowing us to examine a range of possible medication costs. The in‐trial analysis was participant‐level, whereas the lifetime analysis used a Markov model. Both analyses considered value from a US health sector perspective. The incremental cost‐effectiveness ratio (incremental costs divided by incremental quality‐adjusted life‐years) of IPE compared with standard care (SC) was the primary outcome measure. There was incremental gain in quality‐adjusted life‐years with IPE compared with SC using in‐trial (3.28 versus 3.13) and lifetime (10.36 versus 9.83) horizons. Using an IPE cost of $4.59 per day, health care costs were lower with IPE compared with SC for both in‐trial ($29 420 versus $30 947) and lifetime ($216 243 versus $219 212) analyses. IPE versus SC was a dominant strategy in trial and over the lifetime, with 99.7% lifetime probability of an incremental cost‐effectiveness ratio <$50 000 per quality‐adjusted life‐year gained. At a medication cost of $11.48 per day, the cost per quality‐adjusted life‐year gained was $36 208 in trial and $9582 over the lifetime. Conclusions In this analysis, at $4.59 per day, IPE offers better outcomes than SC at lower costs in trial and over a lifetime and is cost‐effective at $11.48 per day for conventional willingness‐to‐pay thresholds. Treatment with IPE should be strongly considered in US patients like those enrolled in REDUCE‐IT USA. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.