Urinary free cortisol (UFC) excretion in 31 patients with major depression is directly compared to UFC levels in 65 patients with panic disorder and 36 controls. Patients with depression demonstrated significantly higher UFC excretion [43 +/- 37 micrograms/g creatinine (cr)] than patients with panic disorder (29 +/- 13 micrograms/g-cr) or controls (22 +/- 10 micrograms/g-cr) (F = 8.5, df = 129, p less than 0.001). Panic patients with a secondary depression (35 +/- 17 micrograms/g-cr) or those with agoraphobia (34 +/- 14 micrograms/g-cr) had UFC levels that were in-between patients with primary major depression and panic patients without these complications (25 +/- 11 micrograms/g-cr). These findings support the hypothesis that patients with major depression, whether primary or secondary, and those with agoraphobia excrete more UFC than patients with uncomplicated panic disorder. This occurs despite the fact that panic disorder might also be expected to raise the stress-responsive hormone cortisol.