Because the formation of sickle cells is dependent on the intracellular concentration of deoxyhemoglobin S, we investigated the possibility of altering or preventing sickle-cell crises by reducing serum sodium so as to cause red cells to swell. In three patients with sickle-cell anemia who had been disabled by recurrent painful crises, sustained dilutional hyponatremia was induced by 1-desamino-8-D-arginine vasopressin (DDAVP) in combination with a high fluid intake. Mean corpuscular hemoglobin concentration fell, and the degree of sickling at low partial oxygen pressure was reduced, as determined by morphologic criteria and by increased oxygen affinity of blood. Chronic hyponatremia (serum sodium, 120 to 125 mmol per liter) reduced the frequency of painful crises, whereas acutely induced hyponatremia abbreviated the duration of crises. These results, although preliminary, are encouraging enough to warrant further study of the safety and effectiveness of induced hyponatremia in the prevention and treatment of sickle-cell crises.