Rationale: We postulated that the p38 pathway is activated in the diaphragm during sepsis and contributes to sepsis induced diaphragm caspase activation and contractile dysfunction. Objectives: This study determined: (a) if endotoxin administration elicits p38 activation in the diaphragm, (b) if cytokines activate p38 in isolated muscle cells, (c) if activation of p38 is accompanied by caspase 8 activation, (d) if inhibition of p38 prevents caspase 8 activation and, (e) if inhibition of p38 prevents diaphragm dysfunction in endotoxin treated animals. Methods: We first evaluated the time course of diaphragm p38 activation following endotoxin in mice. We then determined if p38 inhibitor administration could prevent caspase 8 activation in endotoxin treated mice. We also assessed p38 and caspase 8 activation in C2C12 muscle cells treated with control media or a cytokine mixture, with or without concomitant chemical inhibition of p38 (using SB203580, 25 µM) or loss of p38 function due to cell transfection with a dominant negative p38 genetic construct. Results: Endotoxin administration activated diaphragm p38 (p<0.001) and cytokines activated p38 in C2C12 cells (p<0.05). In both the diaphragm and cells, p38 activation was accompanied by increases in active caspase 8 (p<0.01). Inhibition of p38 with either SB203580 or with a dominant negative p38 construct prevented caspase activation (p<0.001). p38 inhibitors also prevented endotoxin-induced diaphragm weakness (p<.001). Conclusions: p38 modulates cytokine induced skeletal muscle caspase activation.