A double-blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild-to-moderate essential hypertension after a 4-wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of less than or equal to 107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty-nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.