The hemodynamic responses to changes in carotid sinus pressure (CSP) were evaluated in nine pentobarbital-anesthetized dogs during control, endotoxin-treatment, and ibuprofen (after endotoxin) treatment periods. Both carotid sinuses were isolated and perfused at varying pressures with oxygenated blood in the vagotomized animal. Alterations in carotid sinus pressure and the resultant responses were measured at 15-min intervals during a 30-min control period, for 60 min after 1 mg/kg endotoxin, and for 60 min after 10 mg/kg ibuprofen given after endotoxin. The results showed a reduction in calculated gain for mean arterial pressure (MAP) (change in arterial pressure/change in CSP), heart rate, and peripheral resistance (TPR) after endotoxin, without a corresponding reduction in cardiac output (CO) gain. These gain changes were accompanied by a decrease in absolute MAP, CO, and TPR. An indicator for cardiac performance gain also increased. Relatively, arterial pressure was partially maintained by an increase in CO despite a loss in ability to vasoconstrict. Ibuprofen failed to correct the MAP gain, and only partially restored MAP, but shifted a greater relative response to peripheral resistance. To test if TPR would also decrease if the decrease in CO was prevented, three additional animals were studied with a pump in series with the heart to maintain CO; TPR again dropped after endotoxin. The results indicate a loss of peripheral arterial tone after endotoxin, partially restored by ibuprofen. The CO response indicates a peripheral vascular failure rather than a central or carotid sinus failure mechanism.