IL-10 is an anti-inflammatory cytokine that suppresses synthesis of proinflammatory cytokines and their receptors. Here we tested the possibility that TNFalpha-induced hormone resistance in myoblasts might be overcome by IL-10. We found that IL-10 restores myogenesis by suppressing the ability of exogenous TNFalpha to inhibit IGF-I-induced myogenin. This protection occurs without decreasing global activity of TNF receptors since IL-10 does not impair TNFalpha-induced IL-6 synthesis or ERK1/2 phosphorylation. Instead, IL-10 acts to prevent TNFalpha-induced phosphorylation of JNK. These findings demonstrate that IL-10 serves a previously unrecognized protective role in muscle progenitors by overcoming TNFalpha-induced resistance to IGF-I.