The well-established neuroprotective effect of dehydroepiandrosterone (DHEA) has been attributed to its metabolism in the brain to provide estrogens known to be neuroprotective and to enhance memory and learning in humans and animals. However, our previous work showed that the conversion of DHEA to 4-androstenedione (AD), the precursor of estrone (E(1)) and estradiol (E(2)), is very low in several different types of neural cells, and that the main product is 7alpha-hydroxy-DHEA (7alpha-OH-DHEA). In this study, we found that microglia are an exception and produce mainly 5-androstene-3beta,17beta-diol (Delta(5)-Adiol), a C(19) steroid with estrogen-like activity from DHEA. Virtually, no other products, including testosterone (T) were detected by TLC or HPLC in incubations of (3)H-labeled DHEA with the BV2 microglial cell line. Microglia are important brain cells that are thought to play a house-keeping role during the steady state, and that are crucial to the brain's immune reaction to injury and the healing process. Our findings suggest that the microglia-produced Delta(5)-Adiol might have a role in modulating estrogen-sensitive neuroplastic events in the brain, in the absence of adequate local synthesis of estrone and estradiol.