Rationale: Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. Objectives: To determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis induced diaphragm weakness. Methods: Rats (n=8-10/group) were given either: (a) saline (0.5 ml IP), (b) endotoxin (12 mg/kg IP), (c) endotoxin plus MG132 (2.5 mg/kg), (d) endotoxin plus epoxomicin (1 µmol/kg) or (e) endotoxin plus bortezomib (0.05 mg/kg). Animals were sacrificed either 48 or 96 hours after injections and assessment made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Results: Endotoxin increased proteolysis (p<0.001) and MG132, epoxomicin, and bortezomib each prevented this endotoxin induced alteration (p<0.01). Endotoxin induced severe reductions in diaphragm force generation by 48 hours (p<0.01); none of the proteasomal inhibitors prevented loss of force. Endotoxin induced significant reductions in diaphragm mass and protein content by 96 hours (p<0.01); neither MG132 nor epoxomicin prevented loss of mass or protein but bortezomib attenuated the reduction in protein content (p<0.05). Endotoxin increased diaphragm caspase activity (p<0.01); caspase activity remained high when either MG132, epoxomicin or borezomib were given. Conclusions: These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin induced diaphragmatic dysfunction.