The mechanism by which clonidine suppresses plasma renin activity (PRA) was investigated in dogs anesthetized with pentobarbital. Injection of clonidine (1 micrograms/kg) into the cisterna magna decreased PRA from levels stimulated by prior hemorrhage into a blood reservoir to reduce mean blood pressure by 25% (21.7 ng/ml/hr +/- 6.6 SE leads to 11.1 ng/ml/hr +/- 2.4 SE; p less than 0.05). Clonidine reduced heart rate but mean arterial pressure remained constant due to fluid movement between the reservoir and the arterial circulation of the dog. These effects could not be attributed to leakage of clonidine from the cerebrospinal fluid since intravenous administration of the same dose had no effect on PRA. In animals bilaterally splanchnicotomized at the level of the diaphragm, elevated PRA was not reduced by intracisternal clonidine. When return of reservoir fluid was prevented, animals became hypotensive after central clonidine and renin tended to increase. These results indicate that clonidine reduces stimulated renin by a central mechanism that is dependent upon the integrity of the sympathetic innervation of the kidney. Other stimuli for renin release may override the inhibitory effect of central clonidine.