Erythropoietin (EPO) is reported to be mainly produced by renal peritubular interstitial cells. Serum levels of EPO may provide new information on the tubulointerstitial lesions in patients with diabetic nephropathy. We determined EPO, hemoglobin (Hb), and Hb × EPO in 63 diabetic patients who showed normo-, micro- or macroalbuminuria with normal or reduced renal function (creatinine clearance, Ccr, ≥ 60 ml/min or < 60 ml/min). In addition, we followed up Ccr during a mean of 26 months in 13 patients with overt nephropathy and normal renal function. The following results were obtained: (1) Hb, EPO, and Hb × EPO values gradually decreased along with advancing stages of nephropathy, and (2) 6 patients with rapidly decreasing renal function showed significantly lower initial EPO and Hb × EPO values than 7 patients without it (p < 0.01). We conclude that EPO and Hb × EPO values may be a new marker predicting future chronic renal failure in diabetic overt nephropathy.