Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED±3.4,p< 0.0l), associated with an increased cardiac output (5.85–7.73 l/min, SED±0.46,p< 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED±1.03,p< 0.05). Restmg forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED±6.4,p< 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/ min) was also significantly greater after hydrocortisone, increasing from an average of 14.9±2.4 R units before treatment to 35.1±5.5 R units after hydrocortisone (SED±6.0,p< 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume). The increased responsiveness of the peripheral vasculature to reflex pressor stimuli appears to be due to changes in end-organ responsiveness since similar changes occurred with local administration of norepinephrine.