We evaluated the behavioral and physiologic effects of clonidine hydrochloride, a centrally active alpha 2-adrenergic agonist, in two separate studies of patients with panic disorder. In the first study, intravenous clonidine (2 micrograms/kg) and placebo were administered on a blind basis to 12 patients with panic disorder and ten normal controls. Clonidine produced significantly greater decrements in anxiety at one hour in the patients with panic disorder than in the controls. The changes in pulse, blood pressure, and ratings of sleepiness did not differ significantly between patients and controls. In the second study, oral clonidine was administered to 18 patients in a double-blind, flexible-dose treatment trial averaging ten weeks in duration. While anxiolytic effects were noticed in some patients, these effects did not persist in the group as a whole. These two studies indicate that while clonidine has short-term anxiolytic effects in patients with panic disorder, these effects do not persist with long-term administration in most patients.