The value of prazosin and methyldopa administration was compared in 16 patients with essential hypertension during a 6 month randomized, double-blind, parallel trial. Both drugs were administered in combination with hydrochlorothiazide, 50 mg twice daily, until recumbent diastolic blood pressure was decreased to less than 90 mm Hg or the patient was receiving prazosin, 5 mg q.i.d., or methylodpa, 500 mg q.i.d. Addition of either prazosin or methyldopa to hydrochlorothiazide lowered blood pressure significantly and to a similar degree without altering plasma renin activity. Heart rate and weight were significantly increased during prazosin, but not methyldopa, therapy. Symptomatic side effects occurred with equal frequency during treatment with both agents and did not result in alteration or discontinuation of therapy in any patient. A decrease in frequency of administration from q.i.d. to b.i.d. or t.i.d./b.i.d. to q.d. did not adversely affect blood pressure control. Substitution of propranolol for prazosin or methyldopa provided similar antihypertensive effectiveness with a significant decrease in heart rate.