The acute whole-body and peripheral tissue protein response to total parenteral nutrition (TPN) was evaluated before surgery in moderately malnourished patients with stable disease. A primed constant infusion of (U-14C) tyrosine was used in combination with simultaneous measurements of the leg exchange of amino acids, glucose, glycerol, and free fatty acids (FFA). Energy expenditure was measured by indirect calorimetry. Sixteen patients with stable disease and in need of nutritional support were randomized to receive TPN at rates either corresponding to resting requirements (nonprotein calories at 120% of REE with 0.2 g of N/kg/d) or at increased rates (200% of REE with 0.33 g of N/kg/d). Energy expenditure was not affected by the low rate of TPN, but increased with the high rate, with a thermic effect corresponding to 16% of basal levels. Tyrosine flux and incorporation rate into whole-body proteins (protein synthesis) were not altered by the low TPN rate, but increased with the high rate. Estimates of protein breakdown decreased, and tyrosine oxidation increased significantly with both rates of TPN. Protein synthesis was stimulated at the high dose rate only. However, a positive whole-body tyrosine balance (net protein synthesis) measured by the 14C tyrosine technique was associated with a continued negative tyrosine balance across the skeletal muscle compartment in the leg. The results demonstrate that TPN given at rates corresponding to resting needs of 0.2 g of N/kg/day is insufficient to promote protein synthesis in the majority of body proteins. Skeletal muscles may remain in negative protein balance even at high TPN loads. Our results reflect the difficulties of expanding lean body mass through intravenous nutrition in moderately malnourished patients--even those with stable disease.