Progesterone (P(4)) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) have trophic effects and may improve cognitive function. We investigated the role of progestins in a murine model of Alzheimer's Disease (AD) in which transgenic mice co-overexpress a mutant form of amyloid precursor protein (APPswe) and a deletion in presenilin 1 Delta exon 9 (APPswe+PSEN1Deltae9). We hypothesized that: (1) mice with the APPswe+PSEN1Deltae9 mutation would have performance deficits compared to wildtype mice and (2) long-term administration of P(4) would enhance cognitive performance and increase brain progestin levels over placebo. Mice were ovariectomized at 6 months of age and administered placebo or P(4) via subcutaneously implanted pellets. Mice were tested between 9 and 12 months of age for cognitive performance in the object placement, water maze, object recognition, and T-maze tasks and for motor behavior in an activity monitor and then tissues were collected for steroid measurement. P(4) administration increased progestin levels in cortex, diencephalon, midbrain, and cerebellum of wildtype and mutant mice, but increases in 3alpha,5alpha-THP levels in the hippocampus of APPswe+PSEN1Deltae9 mutant mice were attenuated compared to that observed in wildtype mice. APPswe+PSEN1Deltae9 mice showed poorer performance in hippocampus measures (object placement and water maze tasks). In the object recognition and T-maze task, which are mediated by the cortex and hippocampus, P(4) administration improved performance in both wildtype and APPswe+PSEN1Deltae9 mutant mice compared to placebo administration. Thus, APPswe+PSEN1Delta9 mice have deficits in hippocampal performance and capacity to form 3alpha,5alpha-THP in the hippocampus and both wildtype and APPswe+PSEN1Delta9 mice show beneficial effects of P(4) in cortical function and similar capacity to form 3alpha,5alpha-THP in the cortex.