Renal failure causes alterations in thyroid hormone metabolism known as nonthyroidal illness syndrome. In the present study we have examined the effect of a low protein diet (LPD) on circulating levels of hormones of the pituitary-thyroid axis, and tumor necrosis factor alpha (TNF-alpha) in patients with chronic renal failure. Seventeen subjects with conservatively treated chronic renal failure (estimated creatinine clearance 39.5±11.1 mL/min) were studied before and after 8 wk of dietary intervention (0.6 g/kg of ideal body mass protein, 30% of calories derived from fat, 62% of calories derived from carbohydrates, and 10 mg/kg of phosphorus). Body fat and fat-free mass remained unchanged. Urea and TNF-alpha serum concentrations significantly decreased, whereas T3 and total and free T4 serum concentrations increased significantly. Triiodothyronine level after treatment correlated negatively with baseline urea level. Changes in T3, T4, and fT4 serum concentrations as well as calculated peripheral deiodinase activity correlated negatively with their baseline values. Alterations in TNF-alpha correlated positively with protein intake, whereas changes in T4 and T4/TSH were inversely related to vegetal protein intake. In conclusion, low protein, low phosphorus diet, which is often prescribed to patients with moderate impairment of renal function, exerts a beneficial effect on low T3 syndrome coexisting with renal failure. The effect of low protein diet on the pituitary-thyroid axis is dependent on the degree of renal functional impairment and LPD-induced decrease in TNF-alpha may also contribute to the observed effects of dietary treatment.