Acute metabolic acidosis has been shown to inhibit muscle protein synthesis, although little is known on the effect of acidosis of respiratory origin. The aim of this study was to investigate the effect of acute respiratory acidosis on tissue protein synthesis. Rats (n = 8) were made acidotic by increasing the CO2 content of inspired air to 12% for 1 hour. Similar rats breathing normal air served as controls (n = 8). Muscle and liver protein synthesis rates were then measured with L-[ 2H5 ]phenylalanine (150 micromol per 100 g body weight, 40 mol%). The results show that protein synthesis is severely depressed in skeletal muscle (-44% in gastrocnemius, -39% in plantaris, and -24% in soleus muscles, P < .01) and liver (-20%, P < .001) in acidotic animals. However, because breathing CO2 -enriched air was found to lower body temperature by approximately 2 degrees C, in a second experiment (n = 10), the difference in body temperature between treated and control animals was minimized by gently wrapping rats breathing CO2 -enriched air in porous cloths. This second experiment confirmed that respiratory acidosis depresses protein synthesis in muscle (-22% in gastrocnemius, P < .001; -19% in plantaris, P < .01; and -4% in soleus, P = NS). However, no effect on liver protein synthesis could be detected, suggesting that liver protein synthesis may be sensitive to changes in body temperature but is not affected by acute respiratory acidosis for 1 hour. The results show that respiratory acidosis inhibits protein synthesis in skeletal muscle and indicates that acidosis, whether of metabolic or respiratory origin, may contribute to loss of muscle protein in patients with compromised renal or respiratory function.