Protein-restricted diets are prescribed in patients with chronic renal failure (CRF) to alleviate uremic symptoms and to slow the progression of CRF. The potential deleterious effects of protein restriction on nutritional status and clinical outcome of patients with CRF have raised concern. In this study, data were collected from 1985 to 1998 on 239 consecutive patients (age 50.2 +/- 15.6 yr) with advanced CRF (GFR 13.1 +/- 4.8 ml/min) to whom a supplemented very low protein diet (SVLPD) providing 0.3 g protein, 35 kcal, and 5 to 7 mg of inorganic phosphorus per kg per day was administered for a mean duration of 29.6 +/- 25.1 mo. The diet was supplemented with essential amino acids and ketoanalogs, calcium carbonate, iron, and multivitamins. During SVLPD, protein intake decreased from 0.85 +/- 0.23 to 0.43 +/- 0.11 g/kg per d, and body mass index and serum albumin concentration remained unchanged overall. Fourteen patients died during SVLPD; death was unrelated to nutritional parameters. Hemodialysis was initiated after SVLPD in 165 patients at a mean GFR of 5.8 +/-1.5 ml/min. During an average of 54 mo on hemodialysis, mortality was low (2.4% after 1 yr) and correlated to age only, not to nutritional parameters observed at the end of SVLPD. Similar results were obtained in 66 transplanted patients (12 were not dialyzed before transplantation). SVLPD can be safely used in patients with CRF without adverse effects on the clinical and nutritional status of the patients. Due to the preservation of nutritional status and the correction of uremic symptoms, the initiation of dialysis was deferred in these patients. The outcome of patients on renal replacement therapy is not affected by prior treatment with SVLPD during the predialysis phase of CRF.