Primary nephrotic syndrome can, although infrequently, cause severe anemia. However, the mechanisms of the anemia remain unknown. We investigated the mechanism of anemia in nephrotic syndrome by measuring parameters of nephrotic syndrome and anemia in 44 nephrotic patients (male: female; 21:23, average age; 43.6 +/- 20.3 years). Nephrotic patients had significantly lower hematocrits than did healthy controls (43.3 +/- 3.7 vs. 46.8 +/- 3.4% in males, 37.4 +/- 3.5 vs. 40.8 +/- 2.8% in females). Serum erythropoietin (Epo) concentrations were correlated inversely with hemoglobin (Hb), hematocrit (Hct), and red blood cell corpuscle (RBC) counts. Furthermore, serum Epo correlated with the serum iron concentration, but not with the other parameters, such as reticulocytes, serum protein and proteinuria. However, the maximum Epo concentration was less than 100 mU/ml in spite of severe anemia, and this was thought to be inappropriate. On the contrary, urine Epo was not detected by the same method of serum Epo determination in spite of aggressive dialysis with distilled water. When four patients with severe anemia were subcutaneously administered recombinant Epo 6,000 unit two times a week, they showed marked improvement in Hb/Hct/RBC. The precise mechanism of anemia in NS was not elucidated by this investigation, but further study should clarify the causes of the inappropriately low concentration of serum Epo in patients with primary nephrotic syndrome.