Tumor necrosis factor- (TNF) is a proinflammatory cytokine secreted by macrophages in response to bacterial infection. Recently, new evidence has emerged suggesting that stressed or injured myocytes produce TNF that then acts as an autocrine and/or paracrine mediator. TNF receptors type 1 and 2 are present in skeletal muscle cells and muscle cells can secrete, in addition to TNF, other cytokines such as IL-1 or IL-6. Furthermore, the plasma concentration of TNF is elevated in insulin resistant states associated with obesity and type 2 diabetes. Here we show that TNF increased the amount of GLUT4 at the plasma membrane and also glucose uptake in the L6 muscle cell line stably expressing GLUT4 tagged with the c-myc epitope. Regardless of the state of differentiation of the L6 cells, TNF did not affect the rate of proliferation or of apoptosis. The stimulatory effects of TNF on cell surface GLUT4 and glucose uptake were blocked by NFB and p38MAPK pathway specific inhibitors (Bay 11–7082 and SB220025) and these two pathways were stimulated by TNF. Furthermore, although TNF increased IL-6 mRNA and protein expression, IL-6 did not mediate the effects of TNF on cell surface GLUT4 levels, which also did not require de novo protein synthesis. The results indicate that TNF can stimulate glucose uptake in L6 muscle cells by inducing GLUT4 translocation to the plasma membrane possibly through activation of the NFB and p38MAPK signaling pathways and independently of the production of IL-6.