To assess whether dehydroepiandrostenedione (DHEA) substitution, superimposed on GH substitution, improves quality of life of patients with secondary adrenal failure, we studied the effects of DHEA (50 mg/d, 16 wk) vs. placebo (16 wk) in GH- and ACTH-deficient men (n = 15; age, 52 +/- 3 yr), and postmenopausal women (n = 16; age, 61 +/- 2 yr) in a double-blind, placebo-controlled, crossover study. All patients were receiving stable hormone replacement therapy, including a fixed dose of human recombinant GH during the study. The men received testosterone substitution. The female patients did not receive estrogen substitution. At baseline, multiple parameters of quality of life were impaired compared with age- and sex-matched controls, especially in female patients. These parameters were not improved by DHEA treatment. DHEA only slightly improved the depression score (women) and health perception (women and men), although these parameters were not abnormal at baseline. DHEA increased serum IGF-I concentrations in female patients (by approximately 18%; P < 0.001), but not in male patients. In neither group did DHEA affect IGF-binding protein-3 levels. We conclude that DHEA, superimposed on GH substitution, does not substantially improve quality of life in patients with secondary adrenal insufficiency regardless of gender. In addition, DHEA increases IGF-I levels only in estrogen-depleted females, but not in testosterone-treated males, with secondary adrenal insufficiency.