Age-related cognitive decline in postmenopausal women is thought to be partially related to the loss of sex steroids. Like women, old female rhesus monkeys (Macaca mulatta) undergo menopause and show an associated decline in circulating estradiol levels. Similarly, they show an age-related decline in the release of dehydroepiandrosterone (DHEA) from their adrenal glands. Because DHEA acts as a substrate for estradiol synthesis in the brain, it is plausible that DHEA supplementation could enhance cognitive function in the elderly. To test this hypothesis, old ovary-intact female rhesus monkeys were given 5 mg of oral DHEA each morning for 2 months; this administration paradigm was found to recreate the physiological 24-h circulating DHEA levels of young adults. In a delayed matching-to-sample test of recognition memory, with a 240-s retention interval, the regularly-cycling old animals showed a significant improvement in performance after 2 months of DHEA treatment, relative to age-matched irregularly-cycling perimenopausal monkeys (P<0.01, n=3 per group). Irregularly-cycling animals showed no improvement relative to their baseline measurement. These findings demonstrate that 2 months of DHEA hormone supplementation is sufficient to cause a detectable improvement in cognitive function in old females. However, they emphasize that there is a critical period of sensitivity; for DHEA therapy to be effective, it needs to be initiated before the individuals show significant age-related attenuation of estradiol levels. Although the underlying mechanism is unclear, detection of 17β-HSD, 3β-HSD and aromatase enzyme gene expression in the prefrontal cortex and hippocampus, by RT-PCR, suggests that it may involve intracrine conversion of DHEA to estradiol within the CNS.