BACKGROUND: We have often encountered some diabetie patients, in whom the causes of anemia were not clearly identified, despite differential hematologic studies. We, therefore, studied the clinical and biochemical characteristics of diabetic patients with anemia of uncertain cause. The study measured erythropoietin levels in diabetic subjects without significant diabetic renal disease. METHODS: Among 62 medical records of diabetic patients with anemia, showing no evidence of advanced diabetic nephropathy (creatinine clearance > 30 mL/min/1.73m2), the causes of the anemia were evaluated. In addition, we recruited 35 diabetic patients with uncertain causes of anemia, in order to evaluate the serum erythropoietin(Epo) responsiveness. Also, we compared their Epo levels to a group of non-diabetie subjects with similar degree of anemia. RESULT: The causes of anemia were not able to be identified in 28 (45.2 %) of 62 patients. The serum Epo levels of diabetic patients with anemia of uncertain cause (17.6+/-8.1), were significantly lower than those of non-diabetic patients with the same degree of decrease in hemoglobin levels (144.9+/-108.0 mIU/mL, p<0.001). The hemoglobin levels of diabetic patients were correlated with creatinine clearance (r=0.34, p=0.03), serum creatinine levels (r=-0.49, p=0.003), and albumin excretion rate (r=-0.44, p=0.009). But, showed no relation with age, duration of diabetes, glycated hemoglobin, presence of retinopathy or neuropathy. CONCLUSION: We concluded that reduced Epo responsiveness to anemia could explain the anemia present in diabetic patient but without advanced diabetic nephropathy. This may reflect early renal interstitial damage.