The antidiuretic action of chlorpropamide has been amply confirmed since the observations of Arduino and his colleagues in Brazil (1966). We have studied the initial and long-term response of 21 patients with the syndrome of diabetes insipidus. There was a consistent decrease in free water clearance usually to a negative value, which was unaffected by salt restriction. Other clinical studies in these patients, including hypertonic saline infusion, vasopressin administration, water loading and the pharmacological administration of alcohol produced data consistent with the proposed mechanism of action, to potentiate the normal effect of circulating vasopressin on the distal nephron. Free water clearance also became increasingly negative in 4 of 5 normal subjects, but was unaffected in 2 patients with polyuria due to diabetes mellitus. There was a consistent decrease in fluid intake relative to urine output during the initial phase of treatment of diabetes insipidus, suggesting a possible effects via a thirst mechanism, but this effect was not clearly demonstrated in normal subjects. The subsequent clinical course over 3 years of these patients, emphasising the danger of hypoglycaemia in coincident hypopituitarism and in children is discussed.