Six patients with chronic renal failure (glomerular filtration rate 18 +/- 2 ml/min) underwent two 10-day admissions separated by at least 1 yr of outpatient therapy with a very low-protein diet (VLPD) providing 0.28 g protein.kg-1.day-1 plus an amino acid-ketoacid supplement. During each Clinical Research Center admission, subjects completed a 5-day nitrogen balance (BN), and whole body protein turnover was measured during fasting and feeding using intravenous [1-13C]leucine and intragastric [5,5,5-2H3]leucine. Outpatient dietary protein compliance was very good (25 vs. 20 g protein/day or 125% goal), whereas energy intake was only 69% of goal (24 vs. 35 kcal.kg-1.day-1). During the 16 +/- 2 mo of dietary therapy, there were no changes in serum proteins or anthropometrics. BN after > or = 1 yr of dietary therapy was neutral and did not differ from initial values (+0.46 +/- 0.20 vs. +0.55 +/- 0.19 g N/day). Similarly, rates of whole body protein synthesis, degradation, and leucine oxidation after long-term therapy with the VLPD regimen did not differ from baseline values, and neutral BN was maintained by a marked suppression of amino acid oxidation and postprandial inhibition of protein degradation. This is the first evidence that the compensatory changes in whole body protein turnover activated in response to dietary protein restriction are sustained during long-term therapy.