Optimal dietary protein intake for adults with the nephrotic syndrome has not been established; very low-protein diets are believed to be contraindicated. Sixteen patients with the nephrotic syndrome were nevertheless prescribed a very low protein diet (0.3 g/kg) supplemented by 10 to 20 g/d essential amino acids (or, in a few cases, ketoacids) for an average of 10 months (range, 1 to 36 months). In 11 patients with initial glomerular filtration rates (GFRs) < or = 30 mL/min/3 m2 of height (ht)2, significant but modest improvement was seen (on the average) in proteinuria, serum albumin, and serum cholesterol; all 11 eventually went on to dialysis. The other five patients, with initial GFRs of 32 to 69 ml/min/3 m2 of ht2, had either focal segmental glomerulosclerosis, diabetic nephropathy, or, in one patient, both. The nephrotic syndrome associated with these disorders rarely remits spontaneously. However, during the following 3 to 15 months mean proteinuria decreased from 9.3 to 1.9 g/d, mean serum albumin increased from 2.5 g/dL to 3.8 g/dL, and mean serum cholesterol decreased from 415 mg/dL to 255 mg/dL (all P < 0.001). The GFR either remained constant or increased. Four of these five patients have resumed normal or nearly normal diets and remain in remission or near-remission for 6 to 24 months. We conclude that severe protein restriction plus an essential amino acid supplement may induce prolonged remission in adults with the nephrotic syndrome provided that GFR is not severely reduced. The mechanism of this paradoxical response to protein restriction remains to be determined.