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Low-dose hydrocortisone (LDH) enhances aspects of learning and memory in select populations including patients with posttraumatic stress disorder and HIV-infected men. HIV-infected women show impairments in learning and memory, but the cognitive effects of LDH in HIV-infected women are unknown.Double-blind, placebo-controlled, cross-over study examining the time-dependent effects of a single low-dose administration of hydrocortisone (10 mg oral) on cognition in 36 HIV-infected women. Participants were first randomized to LDH or placebo and then received the opposite treatment one month later.Cognitive performance was assessed 30 min and 4 h after pill administration to assess, respectively, nongenomic and genomic effects. Self-reported stress/anxiety and salivary cortisol were assessed throughout sessions.LDH significantly increased salivary cortisol levels versus placebo; levels returned to baseline 4-h postadministration. At the 30-min assessment, LDH enhanced verbal learning and delayed memory, working memory, behavioral inhibition, and visuospatial abilities. At the 4-h assessment, LDH enhanced verbal learning and delayed memory compared with placebo. LDH-induced cognitive benefits related to reductions in cytokines and to a lesser extent to increases in cortisol.The extended benefits from 30 min to 4 h of a single administration of LDH on learning and delayed memory suggest that targeting the hypothalamic–pituitary–adrenal axis may have potential clinical utility in HIV-infected women. These findings contrast with our findings in HIV-infected men who showed improved learning only at the 30-min assessment. Larger, longer term studies are underway to verify possible cognitive enhancing effects of LDH and the clinical significance of these effects in HIV.