This study investigated the effects of progesterone (P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice. The administration of P4 (4 mg/kg) for 3 consecutive days beginning on the 0-2nd day after the first BrdU-injection (BrdU-D(0-2)) produced an approximately twofold increase in the number of 28- and 56-day-old BrdU(+) cells in comparison to the controls, whereas it did not alter the number of 24/48-h-old BrdU(+) cells. P4 preferentially promoted the survival of newborn neurons when administered at BrdU-D(5-7), but not at BrdU-D(10-12) and BrdU-D(15-17). Androstenedione (Ad), testosterone (TE), or estradiol (E2) at the same-dose of P4, when administered at BrdU-D(0-2), could not replicate the effect of P4, while the inhibition of 5alpha-reductase by finasteride did not affect the P4-action, indicating that the P4-effect is exerted by P4 itself but not by its metabolites. On the other hand, the P4R antagonist RU486 partially suppressed the P4-effect, while inhibitors for Src, MEK, or PI3K totally suppressed the P4-effect. Finally, the P4-enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory, which was P4R-dependent. These findings suggest that P4 enhances the survival of newborn neurons through P4R and/or the Src-ERK and PI3K pathways independent of its influence on cell proliferation, which is well correlated with the potentiated spatial cognitive function of P4-treated animals.