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Tumor necrosis factor alpha (TNF-α) is thought to have a key role in metabolic changes of muscle tissue during inflammatory diseases. It is unknown whether TNF-α affects muscle metabolism directly or whether these changes are mediated by secondary mediators. We studied 6 patients undergoing isolated limb perfusion with TNF-α for irresectable soft-tissue sarcoma or in-transit melanomas. Glucose, lactate, ammonia and amino-acid consumption or production were measured in the perfusate during 3 perfusion periods: before, after TNF-α and after the combined administration of TNFα and melphalan. Arterial glucose, lactate, ammonia and aminoacid concentrations were monitored to detect metabolic effects of TNF-α after it entered the systemic circulation. Glucose uptake and lactate release by the limb remained unchanged after the injection of TNF-α alone, as well as after the combination of TNF-α and melphalan. Furthermore, glutamine, alanine, phenylalanine, tyrosine and total amino-acid release into the perfusate did not increase during TNF-α and melphalan treatment, indicating that muscle metabolism was not changed. After the isolated limb perfusion, TNF-α entered the systemic circulation and induced metabolic changes resulting in a doubling of arterial lactate concentrations, decreased arterial glucose concentrations and decreased arterial amino-acid concentrations. Our study shows that regional administration of TNF-α alone or in combination with melphalan does not directly affect muscle glucose and protein metabolism. The data suggest that systemic metabolic changes induced by TNF-α are mediated through secondary, centrally produced, factors. Int. J. Cancer 71:148–154, 1997. © 1997 Wiley-Liss, Inc.