The role of malnutrition in the development of cachexia in rats bearing the Yoshida ascites hepatoma AH-130 was investigated by comparing the changes in tissue protein turnover in these animals with those observed in pair-fed controls. The tumor elicited in rats an early and conspicuous loss of body weight and tissue waste. Protein loss was particularly prominent for the gastrocnemius muscle and the heart and less pronounced for the soleus, while the diaphragm was little affected. Liver, kidneys, and spleen transiently increased in weight then regressed and eventually atrophied, while adrenals were enlarged over the whole experimental period. Protein waste was mainly due to acceleration of tissue protein breakdown, this protein hypercatabolic state being associated with increased cathepsin D activity in liver and gastrocnemius. In pair-fed animals the liver showed a marked protein loss resulting from enhanced catabolism, while the sharp decrease of heart protein content and the less prominent waste of the gastrocnemius were due to a reduction in protein synthesis. The total plasmatic concentration of free amino acids in AH-130-bearing rats was decreased at Day 4, when the tumor was actively proliferating, and returned to control values at Day 10, when the tumor had reached a stationary state. On the contrary, in pair-fed animals total plasma amino acids decreased over the whole experimental period. Plasma branched-chain amino acids were unchanged or even decreased in tumor hosts, while the Gly/Pro ratio was elevated in pair-fed rats. The intracellular concentration of free amino acids was higher in stationary than in exponentially- growing tumors, reflecting the enhanced proteolytic rates observed in stationary tumor cells. On the whole, the results suggest that reduced food uptake and metabolic competition by the tumor are not sufficient to justify the marked hypercatabolism in host tissues during the AH-130 hepatoma growth. The profound differences between tumor-bearing and pair-fed animals suggest that, if malnutrition undoubtedly played a role in this model of cancer cachexia, its effects were overwhelmed and subverted in the frame of the tumor-host interplay that dictated a distinctively peculiar syndrome.