Six adult patients (4 females and 2 males, age range 26-57 years) with Gitelman’s syndrome (GS) were treated with spironolactone 200-300 mg/day (n = 5) and/or amiloride 10-30 mg/day (n = 3) for 1-18 months. The patients had hypokalemia, hyperreninemia, chloride-resistant metabolic alkalosis, renal hypomagnesemia (n = 5), and hypocalciuria (n = 5). Free water clearance studies during maximal water diuresis and furosemide administration were suggestive of a solute reabsorptive defect beyond the loop of Henle. Antialdosterone therapy induced a significant increase of Pk (from 2.6 ± 0.4 to 3.4 ± 0.4 τaM\ p < 0.0001) and a decrease of C_ĸ (from 21.4 ± 13.2 to 10.6 ± 4.8 ml/ min, p < 0.02) and FE_K (from 21.0 ± 13.6 to 13.4 ± 5.7%; p < 0.03); P_Mg increased from 1.38 ± 0.38 to 1.64 ± 0.21 mg/dl (p < 0.03) with a parallel fall of C_Mg (from 5.5 ± 2.3 to 2.9 ± 1.5 ml/min; p < 0.02) and FE_Mg (from 5.7 ± 2.6 to 2.9 ± 0.6%; p < 0.05); arterial blood pH and HCO^-₃ did not change (P = plasma, C = clearance, FE = fractional excretion). The creatinine clearance fell (from 90.5 ± 16.8 to 65.8 ± 20.9 ml/min; p < 0.05), and P_renin rose (from 16.6 ± 8.9 to 35.3 ± 25.3 ng/ml/h;p < 0.02, as did P_aldo (from 26.1 ± 12.3 to 109 ± 82.6ng/dl; p < 0.01), indicating extracellular fluid volume contraction; however no significant clinical symptoms of hypovolemia ensued. Despite increased P_aldo levels, estimated transtubular K gradient in K secretory sites fell (from 8.0 ± 4.0 to 6.7 ± 3.4; p < 0.01), confirming blunted aldosterone tubular effect. At the dosages employed, spironolactone induced a greater increase of P_ĸ (0.81 ± 0.52 mM) than amiloride (0.07 ± 0.41; p < 0.001). In conclusion, antialdosterone therapy is effective in ameliorating hypokalemia and hypomagnesemia in GS. Its effects appear to result mainly from a direct tubular effect on K secretion and Mg reabsorption; extracellular fluid volume contraction appears also to occur during therapy, but has no relevant clinical effects. These results confirm that hypokalemia in GS is more a consequence of increased tubular secretion in the cortical collecting tubule than of impaired tubular K reabsorption; moreover, impaired tubular Mg conservation in GS might also occur in more distal segments of the nephron than previously supposed.