The effects of protirelin administration on the anterior pituitary release of thyrotropin and prolactin were examined in 26 patients with panic disorder and 22 healthy volunteers. There were no differences observed in hormonal responses to protirelin between patients and controls. However, higher Beck Depression Inventory scores were associated with smaller baseline-corrected maximal changes in thyrotropin responses. Cardiovascular responses to protirelin did not differ between a subgroup of 15 patients with panic disorder and 15 age- and sex-matched healthy controls. Although protirelin produced robust increases in heart rate and blood pressure, only one patient with panic disorder experienced a panic attack during the infusion. The hormonal findings suggest that the presence of depressive symptoms may have a significant impact on various indexes of neuroendocrine responsivity and should be taken into consideration when looking at biologic measures in patients with panic disorder. The cardiovascular and behavioral findings do not support the hypothesis that all panic-producing stimuli are nonspecific and suggest that the induction of physical stimuli may be insufficient to produce panic attacks even in susceptible individuals.