Abstract: Background: The REDUCE-IT trial demonstrated the cardiovascular benefit of icosapent ethyl (IPE) vs. mineral oil placebo. However, no data currently exist that assess IPE's effectiveness vs. mixed omega-3 polysaturated fatty acid (OM-3), which would be a more clinicallyrelevant comparison. We aimed to evaluate the real-world effectiveness of IPE vs. OM-3 formulations. Methods: This retrospective active comparator new-user cohort study compared rates of major cardiovascular adverse events (MACE)—a composite endpoint of coronary revascularization, myocardial infarction, stroke and heart failure—among adult new users of IPE vs. OM-3 in 2020-2023 nationwide Veterans Health Administration data. Daily drug exposure was determined via prescription dispensing dates. Outcomes were identified using validated ICD-10-CM-based algorithms. We addressed measured confounding via nearest-neighbor pairwise propensity score (PS) matching. Logistic regression was used to construct PS, as informed by expert-identified variables meeting the disjunctive cause criterion. We used Cox regression to estimate hazard ratios (HRs). Results: Cohorts for analyses of MACE endpoints included 2,144 patients, respectively, in each of IPE and OM-3 exposure groups. Mean age was ~70 years with ~97% male and ~86% white race. Overall mean follow-up time was ~9.4 months. Baseline covariates were generally well-balanced after PS matching. Incidence rates (IRs) for MACE were 37.53 vs 43.18 per 100 person-years among new-users of IPE vs. OM-3. The adjusted HR was 0.62 (95% CI 0.56-0.69). Conclusion: We found a 38% reduction in the rate of MACE in IPE cohort as compared to OM-3. Follow-up studies with larger sample size should aim to generate more precise estimates for individual components of the MACE outcome.