The goal of this pilot study was to evaluate the effect of dehydroepiandrosterone (DHEA) on depressed mood and fatigue in HIV+ men and women, unselected for baseline DHEA level. Secondary questions concerned treatment effects on libido and body cell mass, on serum testosterone levels, and elicitation of short-term side effects. Treatment consisted of an open-label 8-week trial using DHEA doses from 200 to 500 mg/day. Mood responders were maintained for another 4 weeks, then randomized to a double blind placebo controlled 4-week discontinuation trial. Forty-five patients, including six women, entered the trial. Of 32 week 8 completers, mood was much improved in 72%, and 81% were rated responders with respect to fatigue. Response on either parameter was unrelated to baseline serum DHEA level. Twenty-one patients entered the double blind discontinuation phase. No differences in relapse rate between placebo and DHEA groups were observed for either mood or fatigue. Body cell mass increased significantly by week 8, and this improvement was maintained throughout the double blind phase for patients in both treatment conditions. Libido increased significantly as well. DHEA therapy did not have an effect on CD4 cell count or on serum testosterone levels in men. In conclusion, DHEA may be a promising treatment for HIV+ patients with depressed mood and fatigue, although persistence of response even in placebo-treated patients during the discontinuation phase leaves unresolved questions. A parallel group double blind clinical trial is indicated as the next step to more clearly identify therapeutic efficacy.