Backround: It plays important roles to predict vulnerable plaques in patients with acute coronary syndrome (ACS) because the vulnerability of coronary plaques has been relevant to the pathogenesis of ACS. Atheroma with thin-fibrous cap thickness <65 μm estimated by optical coherence tomography (OCT) is thought to be a precursor lesion of plaque rupture. The statin therapy was showed to increase the fibrous cap thickness evaluated by OCT in acute myocardial infarction patients. Recently, several reports have been demonstrated that the intake of fish oil which contained n-3 polyunsaturated fatty acids, including ethyl icosapentate acid (EPA), benefited patients with coronary artery disease clinically. The purpose of study was to examine whether ethyl EPA may have the efficacy to increase in the fibrous-cap thickness similar to statin. Methods: We enrolled consecutive 30 ACS patients fulfilled the following two criteria: (i) LDL-cholesterol <100 mg/dl without statin therapy; and (ii) a non-target lesion with a lipid-rich plaque. They were divided into two groups randomly; the EPA treatment group (n=15) or the control group (n=15). Serial OCT analyses were performed at baseline and nine-month follow-up for a non-PCI lipid-rich plaque lesion. Results: There was no significant difference in patients characteristics and the lipid profile between EPA and control group. Although the fibrous-cap thickness was significantly increased in both the EPA group (169±70μm to 203±53μm, p<0.001) and the control group (175±59μm to 189±61μm, p=0.019) during follow-up period, the relative change in the fibrous-cap thickness from baseline to follow-up of the EPA group was significantly greater than that of the control group (131±32% vs. 108±12%, p=0.017). There was no significant difference in lipid arc from baseline to follow-up in both groups (131±52° to 126±54° vs. 141±49° to 139±50°, p=0.098 vs. 0.485). Conclusion: These findings suggest that EPA treatment is effective in the plaque stabilization with the ACS patients and OCT can help to assess the efficacy of treatment for plaque stabilization.