Increased muscle catabolism is frequently observed in association with inflammatory disease. TNF-α has been implicated as an important messenger for muscle catabolism. Experiments with cultured muscle cells exposed to TNF-α have produced conflicting results. In a mouse cell line (C2C12), effects ranged from catabolic to anabolic. The results reported here offer an explanation for the observed discrepancies. It was found that TNF-α induced proliferation of myoblasts in fully differentiated cultures in low serum media and inhibited adult fast myosin accumulation under all conditions that were tested. Furthermore, TNF-α caused a proliferation dependent increase in total cell protein. Addition of insulin masked the effect of TNF-α on total protein, but not that on adult fast myosin accumulation. Discrepancies between studies can be explained by differences in proliferation rate, the dynamic nature of C2C12 myotube cultures and accumulation of adult fast myosin. The results are consistent with a dual role of TNF-α: stimulation of regeneration by short-term exposure and induction of muscle wasting by prolonged exposure.