The relative benefits and risks of reserpine and guanethidine were compared in patients with thiazide-treated mild to moderate hypertension (diastolic pressure 95-115 mm Hg). Forty-nine ambulant patients )30 men, 19 women) were treated throughout the study with hydrochlorothiazide, 50 mg/day. In this double blind crossover study each drug was added in graded increments until a predetermined therapeutic response was obtained, blood pressure measurements and side effect scores were evaluated biweekly. Major conclusions of the study were: 1) guanethidine, as well as reserpine, will reduce mild to moderate blood pressures to normal; 2) in most cases, side effects which did occur while taking guanethidine or reserpine were well tolerated and neither drug was clearly superior. Side effects associated with larger doses of guanethidine employed in severe hypertension were absent or only slightly bothersome. Thus, guanethidine apppears to have a good benefit-to-risk ratio in the therapy of mild to moderate hypertension and offers a number of advantages over drugs commonly used in this syndrome. This study refutes the common belief that guanethidine must be reserved only for the treatment of more severe degrees of hypertension.