Treatment with cortisol has been found to decrease fatigue and increase feelings of vigor in both patients and healthy male subjects. We obtained self-reports of mood before 35 mg cortisol or placebo ingestion, 70 min later, and after the healthy female subjects performed cognitive tasks for 1 h in a double-blind within-subject study. Cortisol decreased fatigue, increased vigor, and tended to decrease tension. Effects on fatigue were largest after task performance, when fatigue had increased, suggesting that improvement of fatigue by cortisol is observed when subjects are fatigued. This is the first study to demonstrate improvements in fatigue in healthy female subjects; this is particularly relevant because of the high prevalence of hypocortisolimic fatigue syndromes in women and recent evidence that many psychiatric disorders may involve stress-induced hypocortisolemia that is responsive to cortisol replacement.