Eicosapentaenoic acid (EPA) ethyl ester (1.8 g/d) was administered to 16 diabetic patients (5 insulin-dependent and 11 noninsulin-dependent diabetics) for 6 mon. EPA in total plasma fatty acids increased from 4.0±2.4 mol% (mean±SD) to 7.5±3.1 mol% (p<0.001). Albumin excretion, measured with spot urine, was significantly reduced from 65 to 36 mg/g creatinine (geometric means, p<0.001). Fasting blood sugar levels, glycohemoglobin, body weight and blood pressure did not change significantly during the study. There were also no significant changes in serum levels of creatinine, urea nitrogen, total cholesterol and triglycerides. Although no overt hemorrhage was observed in the patients, hematocrit was reduced from 42.6±2.8% to 41.0±3.9% (p<0.02). Ten other similar diabetic patients (4 insulin-dependent and 6 non-insulin-dependent diabetics) were followed as a reference group, not concomitantly, for 6 mon with neither EPA ethyl ester nor placebo. The parameters mentioned above were not changed significantly in this group during 6 mon. EPA administration might retard the appearance of overt diabetic nephropathy.