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Six obese patients, three men and three women, underwent a period of prolonged total starvation with subsequent refeeding. During starvation 24 hr. urinary insulin excretion fell in five of the six patients, and reached abnormally low values in four. On refeeding there was an immediate rise in urinary insulin excretion in all the patients and in four abnormally high levels were reached. After the initial rise the amounts of urinary insulin again fell despite continued and increasing calorie intake, and in three patients returned to the previously low levels. It is suggested that on refeeding there is preferential release of recently formed 'pro-insulin' from a pancreas depleted of normal insulin stores by starvation, and that restoration of a normal pattern of insulin secretion can occur only after normal pancreatic insulin stores have been repleted. A striking difference in response to starvation was observed between men and women.