Tumor necrosis factor (TNF) is elevated following damage to skeletal muscle. Here we provide evidence that TNF acts on muscle cells to induce a state of IGF-I receptor resistance. We establish that TNF inhibits IGF-I-stimulated protein synthesis in primary porcine myoblasts. Similar results were observed in C₂C₁₂ murine myoblasts, where as little as 0.01 ng/ml TNF significantly inhibits protein synthesis induced by IGF-I. TNF also impairs the ability of IGF-I to induce expression of a key myogenic transcription factor, myogenin. The inhibition by TNF of IGF-I-induced protein synthesis and expression of myogenin is not due to direct killing of myoblasts by TNF. Although IGF-I induces an 19-fold induction in tyrosine phosphorylation of the chains of its receptor, TNF does not inhibit this autophosphorylation. Instead, TNF significantly reduces by 50% IGF-I-stimulated tyrosine phosphorylation of two of the major downstream receptor docking molecules, insulin receptor substrate (IRS)-1 and IRS-2. These results establish that low picogram concentrations of TNF acts on both porcine and murine myoblasts to impair tyrosine phosphorylation of both IRS-1 and IRS-2, but not the receptor itself. These data are consistent with the notion that very low, physiological concentrations of TNF interfere with both protein synthesis and muscle cell development by inducing a state of IGF-I receptor resistance.