Studies were performed in anesthetized dogs to determine if the diuretic effect of clonidine results from inhibition of vasopressin secretion. Intravenous clonidine (30 μg/kg) decreased plasma vasopressin concentration (as measured by RIA) from 10.9 ± 1.5 to 5.0 ± 1.1 pg/ml (P > 0.01) in association with a transient increase in arterial blood pressure and a decrease in heart rate. Intravenous administration of two α-adrenoceptor antagonists, piperoxane and phentolamine, virtually abolished the pressor effect of clonidine but did not prevent the suppression of plasma vasopressin concentration. Clonidine decreased plasma vasopressin concentration from 11.9 ± 3.1 to 3.3 ± 1.0 pg/ml in the phentolamine-treated dogs (P > 0.01) and from 18.1 ± 4.5 to 12.4 ± 3.6 pg/ml in the piperoxane-treated dogs (P > 0.05). These results provide direct evidence that the diuretic effect of clonidine results from inhibiti on of the secretion of vasopressin. This inhibition does not appear to be a consequence of the pressor effect of the drug but may result from a direct action in the central nervous system.