BACKGROUND: We hypothesized that the additional administration of eicosapentaenoic acid (EPA) in patients with stable coronary artery disease (CAD) receiving statin has the potential to lower the serum pentraxin 3 (PTX3) level, an indicator of plaque stabilization. METHODS: We randomly assigned CAD patients already receiving statin therapy to an EPA group (1800 mg/day, n = 53) or control group (n = 53). RESULTS: No significant difference was found in the change in the plasma PTX3 level between the groups. However, in a subgroup analysis, a significant percentage reduction in the plasma PTX3 level was observed in patients receiving strong statin compared with the patients receiving moderate statin in the EPA group (-5.6 vs. 14.7 %, p = 0.0082), while no such difference in the percentage change in the plasma PTX3 level was noted between the two same statin subgroups in the control group. A multiple logistic regression analysis identified the addition of EPA to ongoing strong statin treatment as an independent predictor of PTX3 level reduction. Furthermore, even in patients with relatively well-controlled serum lipid levels, pretreatment with EPA added to ongoing statin therapy reduced serum non-high-density lipoprotein cholesterol and triglyceride-rich lipoproteins as residual risk factors. CONCLUSION: Through this study design, the results could not support the hypothesis that adding EPA in patients with stable CAD receiving varying degrees of statin treatment reduces the plasma PTX3 level comprehensively. However, addition of EPA to ongoing strong statin treatment, but not ongoing moderate statin treatment, may reduce the plasma PTX3 level, possibly leading to coronary plaque stabilization. CLINICAL TRIAL REGISTRATION INFORMATION: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010452.