Influence of dietary protein deficiency on the anti-inflammatory and ulcerogenic effects and on the kinetics of phenylbutazone was studied in male Sprague-Dawley rats fed ad libitum a 21% (control) or a 5% (low) protein diet for 3 weeks. A low protein diet fed to a decrease in body weight gain, plasma proteins, albumin, globulins, hepatic total and microsomal proteins and in cytochrome P-450. Phenylbutazone produced a greater ulcerogenic effect in rats fed a low protein diet than in control rats; its anti-inflammatory effect did not increase. Plasma t 1/2 of phenylbutazone was longer in protein-deficient rats than in control rats. Dietary protein deprivation led to a decrease in the plasma clearance and plasma protein binding of phenylbutazone but did not lead to a change in its bioavailability. No relationship between the severity of gastric ulceration and the concentration of phenylbutazone or oxyphenbutazone in the stomach tissue was found in any animal of the two groups. The increased susceptibility of protein-deficient rats to the ulcerogenic effect of phenylbutazone was reversible and was not observed when these animals were fed a control diet for 3 weeks. It is concluded that a dietary protein deficiency increases the ulcerogenic toxicity of phenylbutazone relative to its useful anti-inflammatory effects.