Sixty-five patients with panic disorder and 37 matched controls collected 24-hour urine specimens for measurement of urinary free cortisol. Although patients with panic disorder had significantly higher urinary free cortisol levels than control subjects, this difference was accounted for by panic disorder patients with concomitant depression, agoraphobia, or both. Urinary free cortisol excretion was not related to the age of onset of panic disorder, the number of spontaneous panic attacks, or the degree of impairment associated with the disorder. They were related, however, to the level of symptoms on both the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety in the entire group of panic patients, but this relationship disappeared when those patients with the complications of agoraphobia and depression were excluded. These data suggest that, as with primary depression, depression secondary to panic disorder, as well as to agoraphobia in panic disorder patients, is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.