Cachectin/tumor necrosis factor has been implicated as a mediator of lethal endotoxemia, but the metabolic and hemodynamic responses to this macrophage-derived peptide have been incompletely characterized. Cachectin was administered by intra-arterial infusion in two groups of beagle dogs at lethal (100 micrograms per kilogram) and sublethal (10 micrograms per kilogram) doses. The infusion produced serum cachectin levels (1 to 50 nanomoles per liter) similar to those achieved after experimental endotoxemia. The lethal response to cachectin was characterized by progressive hypotension, shock and death within three hours. Histopathologic findings included acute inflammation of the pulmonary interstitium, intravascular thrombosis with hemorrhagic necrosis, adrenal medullary necrosis and acute renal tubular necrosis. Cachectin infusion precipitated significant increases of plasma catecholamines, cortisol and glucagon in a dose response manner. Cachectin infused directly into the isolated hindlimb mediated reductions of skeletal muscle resting transmembrane potential and stimulated lactate efflux. Cachectin appears to occupy a crucial role in physiopathologic responses to infection, and likely participates in the mobilization of host energy stores, intravascular depletion and shock after lethal endotoxemia.