Abstract Background Treatment with eicosapentaenoic acid (EA) has been shown to reduce the incidence of cardiovascular adverse events (MACE) in patients at high cardiovascular risk with mildly to moderately elevated triglyceride values (>135 mg/dl) and non-elevated (<100 mg/dl) low-density lipoprotein cholesterol (LDLc). Methods We performed a multicenter and retrospective study using the ongoing registries of acute coronary syndrome (ACS) patients of 7 hospitals from Spain. Patients with LDLc <100 mg/dl and triglycerides >135 mg/dl were analyzed as candidates to EA. Results We included 14,483 patients discharged after an ACS, mean age 67.5 (13.3), 28.1% women and 30.4% with an ST-elevation ACS. Mean LDLc was 99.8 (38.5) mg/dl and median triglycerides 120.5 (interquartile range 90-197) mg/dl. A total of 3,028 (20.9%) were classified as candidates for EA, and they had the same mean age (p=0.87) but significantly higher prevalence of diabetes (35.1% vs. 21.9%), dyslipidemia (63.5% vs. 50.1%), previous coronary heart disease (CHD) (25.9% vs. 13.9%), or heart failure (HF) (3.6% vs. 2.5%). Candidates less frequently had an ST-elevation ACS (26.6% vs. 34.1%; p=0.02) and the incidence of Killip >1 was equivalent in candidates vs. non-candidates (16.6% vs. 17.7%; p=0.15). Median follow-up was 1223 (interquartile range 570-2040) days. All-cause mortality was 15.0% (n= 2,166), and 34.71% (n=5,019) of the patients experienced a first MACE. Candidates for EA had higher mortality (18.4% vs. 14.0%; HR: 1.22 95% CI 1.11-1.35) and MACE (39.0% vs. 33.6%; HR 1.14 95% CI 1.06-1.21) rates. Multivariate analysis (figure), adjusted for age, sex, diabetes (DM), previous coronary heart disease (CHD) or heart failure (HF), and medical treatments at discharge, identified an independently higher risk for all-cause mortality among candidates for EA (HR: 1.15 95% CI 1.04-1.26) [Figure 1] and for MACE (HR: 1.14 95% CI 1.05-1.20). The risk was consistent in all subgroups except for the case of mortality, but not for MACE, and previous ACS (figure 2) were a significant interaction (p=0.01) was observed Conclusions Approximately 20% of patients discharged after an ACS could be candidates for EA, and this subset of patients are at higher risk of death or a first MACE.