When somatostatin was infused into the left renal artery of anaesthetized, hydropenic dogs in doses ranging from 1 to 10 micrograms/min, it produced an increased flow of a more dilute urine from the ipsilateral kidney. Similar infusions in dogs undergoing a maximal water diuresis had no effect. If aqueous antidiuretic hormone (ADH) was administered intravenously into water-loaded dogs prior to the intraarterial infusion of somatostatin, this latter peptide was able to produce an augmented flow of a more dilute urine from the ipsilateral kidney. If the left kidney was made to excrete a concentrated urine in the face of maximal water loading by restricting arterial perfusion, then the infusion of somatostatin had no effect on urinary dilution, though this peptide could increase water excretion in hydropenic dogs when the left kidney was similarly restricted as to arterial inflow. In dogs undergoing a water diuresis that were given cyclic AMP (4 mg/min) into the left renal artery, a decrease in ipsilateral water excretion was observed. The subsequent infusion of somatostatin produced no urinary dilution. We conclude that somatostatin increases renal water excretion by antagonizing the ADH effect on the renal tubule, and that this event probably occurs at a pre-cAMP site within the cell.