✓ The present study was undertaken to determine if estrogens protect female rats from the neurodegenerative effects of middle cerebral artery (MCA) occlusion. The rats were ovariectomized and 7 or 8 days later various estrogen preparations were administered before or after MCA occlusion. Pretreatment with 17β-estradiol (17β-E2) or a brain-targeted 17β-E2 chemical delivery system (CDS) decreased mortality from 65% in ovariectomized rats to 22% in 17β-E2—treated and 16% in 17β-E2 CDS—treated rats. This marked reduction in mortality was accompanied by a reduction in the ischemic area of the brain from 25.6 ± 5.7% in the ovariectomized rats to 9.8 ± 4% and 9.1 ± 4.2% in the 17β-E2—implanted and the 17β-E2 CDS—treated rats, respectively. Similarly, pretreatment with the presumed inactive estrogen, 17α-estradiol, reduced mortality from 36 to 0% and reduced the ischemic area by 55 to 81%. When administered 40 or 90 minutes after MCA occlusion, 17β-E2 CDS reduced the area of ischemia by 45 to 90% or 31%, respectively. In summary, the present study provides the first evidence that estrogens exert neuroprotective effects in an animal model of ischemia and suggests that estrogens may be a useful therapy to protect neurons against the neurodegenerative effects of stroke.