There is evidence that the kidney has a major role in the formation of the arginine used for extrahepatic protein synthesis. The effects of arginine-free diets were studied, therefore, in female Sprague-Dawley rats made uremic by partial left-renal artery ligation and contralateral nephrectomy. Uremic and sham-operated control rats were fed diets with amino acids proportioned as in casein or similar isonitrogenous diets in which the arginine was replaced by glutamic acid and alanine. Weight gain and the food efficiency ratio were determined, and 6 weeks after nephrectomy, a pulse dose of 14C-guanido arginine was administered. The rats were killed 2 hours later, and the radioactivity of proteins in various tissues was determined. Free arginine levels in tissues were also measured. Control rats fed diets devoid of arginine had reduced growth and a low food efficiency ratio. Free arginine levels in tissues and 14C-arginine incorporation into tissue protein in these rats were not different from controls receiving arginine except that 14C-incorporation into brain protein was decreased. Uremic rats fed an arginine-containing diet had a reduced growth rate as compared to control rats, and 14C-incorporation into brain protein was less. In uremic rats, when arginine was removed from the diet, there was no further effect on weight gain but the plasma arginine level was decreased and the incorporation of 14C-guanido arginine into protein of muscle and of kidney was reduced. Hence, the effects of an arginine-free diet appears to be different in chronically uremic as compared to control rats.