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Objective: The adrenal excretion of cortisol in animals is dependent on the production of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus. The a priori hypothesis of this study was that hypothalamic regional cerebral blood flow (rCBF) would correlate positively with salivary cortisol levels in patients with social anxiety disorder (SAD) during anxiety provocation. Another objective was to evaluate whether salivary cortisol levels correlated with rCBF in other brain areas. Method: Regional CBF was measured with oxygen-15-labeled water and positron emission tomography during a public speaking task before and after placebo treatment in 12 subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined SAD. Cortisol concentrations in saliva were measured 15 minutes after the task. The a priori hypothesis of a salivary cortisol-dependent activation of the hypothalamus was studied with region-of-interest analysis. In addition, the covariation between rCBF and salivary cortisol was studied in the whole brain using the general linear model. Results: The region-of-interest analysis revealed a positive correlation between salivary cortisol and hypothalamic rCBF. In the whole brain analysis, a positive covariation between rCBF and salivary cortisol levels was found in a midbrain cluster encompassing the hypothalamus with its statistical maximum in the mamillary bodies. Negative covariations were observed in the medial prefrontal cortex as well as in the motor and premotor cortices. Conclusion: Like in animals, stress-induced cortisol excretion in humans may be inhibited by activity in the medial prefrontal cortex and enhanced by activity in the hypothalamus.