The origin and regulation of angiotensinogen in cerebrospinal fluid (CSF) was investigated in rats by measuring renin substrate in plasma and CSF under different experimental conditions. Nephrectomy (NX) increased the circulating and the central angiotensinogen levels. There was no correlation between the individual values of plasma and CSF. Adrenalectomy (ADX) diminished and hydrocortisone treatment augmented the angiotensinogen levels in plasma and CSF. The combination of ADX and NX caused a dissociation between peripheral and central angiotensinogen, since the values were elevated in plasma but unchanged in CSF. After the application of the converting-enzyme inhibitor captopril a significant decrease of angiotensinogen was observed in plasma only. A specific radioimmunoassay for renin substrate of rat plasma also recognized CSF angiotensinogen. There was a linear correlation between the CSF substrate levels obtained by direct and indirect measurement. In conclusion, CSF angiotensinogen appears to be immunologically similar to the plasma molecule. The angiotensinogen levels in CSF and plasma may be affected in parallel but can nevertheless be dissociated from each other.