Nephrogenic diabetes insipidus (NDI) is a frequent complication in patients receiving long-term lithium therapy. Both thiazide diuretics and amiloride may reduce the polyuria, but the use of each is associated with problems. We report the results of a clinical trial using the nonsteroidal anti-inflammatory drug indomethacin to treat a patient with well-documented lithium-induced NDI that persisted following cessation of lithium treatment. The administration of a single dose of indomethacin resulted in a dramatic decrease in urine volume and increase in urine osmolality that persisted for several hours, and was independent of renal hemodynamic changes. Subsequently, the patient experienced a sustained, favorable effect on her polyuria during long-term (3 months) indomethacin therapy without a deleterious effect on her renal function. Indomethacin may be a useful therapeutic tool for the amelioration of lithium-induced NDI.