Sex differences have been observed in the outcome after ischemia that are believed to be attributable to sex steroid hormones. The present study investigated the possible benefits of progesterone administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received progesterone (8 mg/kg, intraperitoneally) or vehicle (dimethyl sulfoxide) 1, 6, and 24 hours after MCAO. The lesion volume at 48 hours after MCAO was significantly reduced (P < 0.05) in progesterone-treated mice compared with vehicle-treated mice. All other mice underwent tests of well being (survival rate and body weight recovery), motor ability (grid test and rotarod), and cognitive ability (water maze) for up to 21 days. MCAO significantly worsened outcome in all of these tests compared with shams. Progesterone treatment was beneficial in that compared with vehicle, it significantly improved survival rate, weight recovery, and motor ability. This improvement was most apparent during water maze testing, where progesterone-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate beneficial effects of progesterone administration after cerebral ischemia and illustrate the need to further investigate the mechanisms of progesterone action.