In hypoaldosteronemic patients with chronic renal insufficiency, administration of a mineralocorticoid steroid such as fludrocortisone can ameliorate hyperkalemia and metabolic acidosis, but this therapy is not always safe owing to the deleterious consequences of extracellular fluid volume expansion resulting from mineralocorticoid-induced sodium chloride retention. In the present study of 8 patients with renal hyperchloremic acidosis, mild hyperkalemia and chronic glomerular insufficiency, we evaluated the therapeutic effect of chronic administration of a natriuretic/chloruretic agent, furosemide, a renoactive drug that is known to increase renal acid excretion in experimental animals without increasing body content of sodium chloride. 4 patients had hyporeninemic hypoaldosteronism. During 8 days of treatment in 6 patients who received furosemide alone, metabolic acidosis was significantly ameliorated. Urinary net acid excretion increased, except in the 2 patients who had the most severe hypoaldosteronism. For the group as a whole, the cumulative change in net acid excretion correlated positively with the rate of aldosterone excretion (r = 0.94, p less than 0.01). Thus, the aciduric response to furosemide is attenuated by aldosterone deficiency. When furosemide was administered in combination with fludrocortisone (4 subjects), an amelioration of metabolic acidosis occurred that was greater than that observed in the group treated with furosemide alone. Combined therapy ameliorated acidosis in the patient with the most severe degree of hypoaldosteronism, the same patient in whom administration of furosemide without fludrocortisone was ineffective even after 6 months of treatment. The findings in this study indicate that chronic furosemide therapy, alone or in combination with fludrocortisone, is a safe and effective means of ameliorating metabolic acidosis in patients with chronic renal insufficiency, including those with hypoaldosteronism.