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Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone\/corticotropin-releasing factor (Dex\/CRF) test, in analogy with research in affective disorders.<\/jats:p><\/jats:sec><jats:sec id=\"S0033291707001444_sec_a002\"><jats:title>Method<\/jats:title><jats:p>Thirty-four well-characterized female CFS patients and 25 healthy control subjects participated in the low-dose Dex\/CRF test. Current major depressive episode was an exclusion criterion. History of early-life stress (ELS) was assessed with the Structured Trauma Interview.<\/jats:p><\/jats:sec><jats:sec id=\"S0033291707001444_sec_a003\" sec-type=\"results\"><jats:title>Results<\/jats:title><jats:p>Salivary cortisol responses after 0.5\u00a0mg Dex were lower in CFS patients than in controls (before 100\u00a0\u03bcg CRF,<jats:italic>p<\/jats:italic>=0.038; after 100\u00a0\u03bcg CRF,<jats:italic>p<\/jats:italic>=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF,<jats:italic>p<\/jats:italic>=0.005; after CRF,<jats:italic>p<\/jats:italic>=0.008).<\/jats:p><\/jats:sec><jats:sec id=\"S0033291707001444_sec_a004\" sec-type=\"conclusion\"><jats:title>Conclusions<\/jats:title><jats:p>CFS is globally associated with reduced cortisol responses in the combined low-dose Dex\/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and\/or a reduced central HPA axis drive in CFS. 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