The antihypertensive effect of once and twice daily hydrochlorothiazide administration was compared in 24 ambulatory patients with essential hypertension. Hydrochlorothiazide 100 mg daily taken as a single morning dose or as a twice daily divided dose was administered to 24 previously diagnosed hypertensive patients in a double-blind cross-over fashion for 12 weeks. No patient received other antihypertensive agents or medications known to influence blood pressure. Sitting and standing blood pressure, weight, pulse, tablet count, and subjective complaints of side effects were obtained at study weeks 3 and 6 on each treatment schedule. There was no significant difference between the mean sitting systolic (133 and 131 mm Hg) or diastolic (85 and 84 mm Hg) blood pressure measurements at study weeks 3 and 6 for each treatment schedule. Comparison of standing mean systolic and diastolic blood pressure and mean arterial pressure produced similar results. Subjective complaints of medication side effects, including orthostasis or urinary frequency, did not differ between treatment schedules. This study suggests that hydrochlorothiazide may be effectively administered once daily for the treatment of hypertension.