Acute moderate hemorrhage (15 ml/kg withdrawn over 10 min) was used to study stress hormone changes in blood and cerebrospinal fluid (CSF) of conscious sheep with chronic indwelling intracerebroventricular catheters. Mean plasma arginine vasopressin (AVP) and ACTH rose 150- and 14-fold, respectively, above basal values to peak levels at 20 min after onset of hemorrhage. A smaller (4- to 5-fold) rise occurred in plasma angiotensin II (AII) to peak levels at 10 min. The corticosteroid response (cortisol and aldosterone) occurred later (peak at 45 min) and was consistent with the dependence of these steroids on plasma ACTH and AII changes. Increases in plasma epinephrine and norepinephrine were small and transient. Compared to changes in plasma, changes in CSF hormone levels after hemorrhage were small and independent of plasma concentrations. Mean CSF AVP increased to peak levels at 15 min whereas rises in CSF ACTH, AII-like immunoreactivity, and cortisol were slower and delayed in comparison with the patterns observed in plasma. Despite evidence of increased sympathetic activity, and rise in plasma catecholamines, CSF epinephrine fell after hemorrhage and CSF norepinephrine did not change. These results show that in conscious sheep rapid and major increases in plasma AVP, ACTH, and AII follow acute moderate hemorrhage. Concomitant changes in CSF hormone levels are small and delayed. With the possible exception of AVP it appears unlikely that the acute systemic hormone response to hemorrhage is determined by hormone changes in CSF.