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Fatigue is one of the most common and distressing symptoms experienced by cancer patients and survivors. However, the etiology of cancer-related fatigue has not been determined. In previous studies, we have shown alterations in morning serum cortisol levels and diurnal cortisol rhythms in fatigued breast cancer survivors compared with nonfatigued control subjects. The purpose of the current study was to evaluate cortisol responses to an experimental psychologic stressor in fatigued and nonfatigued survivors.Participants included 27 breast cancer survivors (11 fatigued, 16 nonfatigued). All had completed cancer treatment at least 3 years previously and were currently healthy with no evidence of recurrence. A standardized laboratory stressor, the Trier Social Stress Test (TSST), was administered during a 90-minute afternoon session. Saliva samples and autonomic measures (heart rate, blood pressure) were collected at 15-minute intervals throughout the session.Fatigued survivors showed a significantly blunted cortisol response to the stressor compared with nonfatigued survivors, controlling for depression and other potential confounds (p <.05). No differences in autonomic measures were observed.These results, together with our earlier findings, suggest a dysregulation in hypothalamic–pituitary–adrenal (HPA) axis responsiveness among breast cancer survivors with enduring fatigue. Although the sample size was small, results suggest that attention to the HPA axis may be important for understanding cancer-related fatigue.