A recent study showed eicosapentaenoic acid (EPA) is a promising treatment for prevention of coronary events in hypercholesterolemic patients. Meanwhile, a high red blood cell distribution width (RDW) is a known risk factor for cardiovascular events. However, few studies have addressed the association between EPA levels and RDW. We examined whether EPA administration reduced the levels of RDW in patients with ischemic heart disease (IHD). We retrospectively analyzed the data of 66 EPA-treated IHD patients, and these EPA-treated patients were compared with control IHD patients. The median follow-up period was 189 days in EPA-treated patients. All patients were not associated with anemia. In the follow-up period, the ratio of EPA levels to arachidonic acid levels (EPA/AA) was significantly increased. A significant decrease was observed in RDW at follow-up [ΔRDW (%); EPA vs. control = -0.34 ± 0.84 (SD) vs. 0.08 ± 0.86, P < 0.01]. These RDW changes were more marked in diabetic patients with high serum levels of high-sensitive C-reactive protein (hs-CRP) [ΔRDW (%); EPA vs. control = -0.53 ± 0.69 vs. 0.56 ± 0.85, P < 0.01]. There was no correlation between the amount of change in EPA/AA and RDW (R = 0.037, P = 0.32), but a significant negative correlation was observed in diabetic patients with high hs-CRP levels (N = 14, R = -0.506, P = 0.046). In conclusion, EPA has the potential to reduce RDW in IHD patients. This effect was intensified especially among diabetic patients with high hs-CRP levels. IHD patients with high RDW levels may be suitable for treatment with purified EPA.