BACKGROUND: Considerable research implicates over-activity of the hypothalamic-pituitary adrenal axis in the pathophysiology of adult mood and anxiety disorders. The current study evaluates the association between salivary cortisol concentrations and response to carbon-dioxide inhalation in children and adolescents with anxiety disorders, mood disorders, or no psychiatric illness. The central question was whether response to carbon-dioxide inhalation is associated with levels of hypothalamic-pituitary adrenal axis activation. If confirmed, this would relate hypothalamic-pituitary adrenal axis activation in juveniles, as in adults, and response to a well-studied respiratory procedure. METHODS: Serial salivary cortisol samples were examined in 98 subjects (ages 9-17 years), including 62 subjects with an anxiety and/or mood disorder and 36 nonpsychiatrically ill comparisons. Samples were obtained upon arrival at the laboratory, following a tilt test, then before and immediately after a standard 5% carbon dioxide inhalation procedure. RESULTS: Salivary cortisol levels pre-carbon-dioxide inhalation were significantly higher in patients sensitive to the anxiogenic effects of carbon dioxide (n = 20) than in patients who did not respond to carbon dioxide (n = 42) and in healthy subjects, none of whom were sensitive to carbon dioxide (n = 36); cortisol concentrations in the latter two groups were indistinguishable. Salivary cortisol did not increase during carbon-dioxide inhalation, irrespective of diagnostic group or degree of reactivity to the procedure. CONCLUSIONS: The current data resemble data from studies of laboratory-induced panic among adult patients. In both groups, activation of the hypothalamic-pituitary adrenal axis is associated with the response to a standardized stressor. Similarly, as in adults, carbon-dioxide inhalation in juveniles does not produce a significant change in hypothalamic-pituitary adrenal axis activation.