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Key Points The bulk of evidence points to modest reductions in cortisol levels in some cohorts of patients with chronic fatigue syndrome (CFS), and these changes are more apparent in women than in men Underlying the reduction in cortisol levels is a hypothalamic–pituitary–adrenal (HPA) axis with attenuated diurnal variation, enhanced negative feedback and blunted response to challenges Low cortisol levels have clinical relevance as they might contribute to symptoms—along with other factors—and are associated with a worsened outcome of currently recommended treatments for CFS A multidimensional etiological model remains most probable, with low cortisol levels occurring at a later stage of the illness, moderated by factors such as activity levels, depression, early-life stress and psychotropic medication Cortisol levels can be increased by treatment with cognitive behavioral therapy, potentially because of reversal of some moderating factors Further improvements in research designs remain necessary to fully understand HPA axis dysfunction in CFS This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 12 print issues and online access $189.00 per year only $15.75 per issue Buy this article Purchase on SpringerLink Instant access to the full article PDF