Ketoacids (KA) and recombinant human erythropoietin (rHuEPO) may each, on their own, influence the metabolic status of patients with chronic renal failure (CRF). A long-term prospective randomized study was designed to monitor the metabolic and nutritional status and progression of CRF using three therapeutic protocols: (A) low-protein diet (LPD) with 0.6 g of protein and 35 kcal/kg/day, with recombinant human erythropoietin (rHuEPO) at a dose of 40 U kg/week and keto acids (KA) 100 mg/kg/day, (Group I), (B) LPD and rHuEPO (Group II), and (C) LPD only (Group III). A total of 105 patients (50M/55F), aged 26-78 years, CCr 22-36 ml/min, were monitored at the beginning, and at every 6 months for 3 years in the above three study groups. Group I comprised 35 patients, Group II 38 patients and Group III 32 patients. During follow-up, a significantly smaller decrease in GFR (CCr, Cin) and in I/SCr, and an increase in serum albumin, transferrin, leucine, body mass, index and HDL-cholesterol were found in Group I (all p < 0.01). In addition, significant decreases were also seen in proteinuria, renal fractional leucine excretion and serum triglycerides level (p < 0.01). Co-administration of LPD, rHuEPO and KA thus constitutes an effective alternative to conservative management of CRF, delaying in follow-up period progression of renal failure and correction of metabolic parameters.