A diet containing about 40 kcal/kg, 0.6 g/kg of protein, 700 mg of phosphorus, and 1,000 to 1,500 mg of calcium (orally supplemented) was prescribed to three groups of patients with chronic renal failure for 6 to 76 months. The mean serum creatinine values were 2.18 mg/dl in group 1 (25 patients), 4.24 mg/dl in group 2 (20 patients), and 6.10 mg/dl in group 3 (8 patients). An additional group of 30 patients (group 4) who had followed no specific dietary treatment for 3 to 72 months was taken as control. The plots of reciprocal serum creatinine against time gave slopes of -0.0008, -0.0010, and -0.0041 in the three groups of patients on the protein-restricted diet, and a slope of -0.020 in the patients on the free diet. The differences between the slopes in patients in groups 1, 2, and 3 versus that in patients in group 4 are statistically significant (analysis of variance and F ratio: P less than 0.01). During the follow-up period a decline in reciprocal serum creatinine greater than the mean values in the whole group was observed in 37.5% of patients in group 3, in 20% of those in group 2, and in only 12% of those in group 1. Thus, the degree of functional renal deterioration is critical in modulating the effects of dietary protein and phosphorus restriction. Several nonimmunologic factors, including hypertension, infection, electrolyte abnormalities, and low-calorie intake, appeared to play an important role in influencing the rate of progression of renal failure in patients on dietary protein restriction.