The effects of treatment with hydrochlorothiazide combined with amiloride were compared to hydrochlorothiazide treatment alone in 2 brothers with congenital nephrogenic diabetes insipidus. Whereas both modalities of treatment resulted in reduction in voiding frequency and urine volume, decrease in daily fluid intake and increase in urine osmolality, the two-drug combination was found to be superior to hydrochlorothiazide alone by preventing urinary potassium losses, hypokalemia, and alkalosis. It was also found that amiloride had a certain additive effect to the thiazide in terms of increasing initial urinary sodium excretion, reducing urine volume and free water clearance, and lowering serum sodium concentration and osmolality. Similar comparison of the hydrochlorothiazide-amiloride regimen to treatment with the hydrochlorothiazide-tolmetin combination in 1 of the patients revealed that the effectiveness of both diuretic modalities was close with slight advantage of the former. Treatment of the 2 patients for 10 months with hydrochlorothiazide and amiloride showed no adverse effects and consistent reduction in fluid intake and urine volume. It is concluded that the hydrochlorothiazide-amiloride regimen is superior to hydrochlorothiazide alone and can be a satisfactory alternative to the hydrochlorothiazide-prostaglandin synthetase inhibitor combination in the treatment of congenital nephrogenic diabetes insipidus.