We often encounter diabetic patients with anemia 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 and measured erythropoietin (Epo) concentrations in 35 diabetic subjects without significant diabetic renal disease. Among 62 medical records of diabetic patients with anemia, showing no evidence of advanced diabetic nephropathy (creatinine clearance > or = 30 mg/kg/1.73 m2), the causes of the anemia were not able to be identified in 28 cases (45.2%). In addition, we enrolled 35 diabetic patients with uncertain causes of anemia in order to evaluate the serum Epo responsiveness to anemia, and compared levels to a group of non-diabetic subjects also with anemia. The serum Epo concentrations of diabetic patients (17.6 +/- 8.1 mIU/ml) were significantly lower than those of non-diabetic patients with similar degree of decrease in hemoglobin concentrations (144.9 +/- 108.0 mIU/ml, P<0.001). The hemoglobin concentrations of diabetic patients correlated with creatinine clearance (r = 0.34, P = 0.03), serum creatinine (r = -0.49, P = 0.003) and albumin excretion rate (r = -0.44, P = 0.009), but showed no relation to age, duration of diabetes, glycated hemoglobin, presence of retinopathy or neuropathy. 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.