© 2017 Elsevier Inc. All rights reserved. It is known that estrogen can mitigate neurological injury. However, to optimize estrogen's benefits, it must be administered as soon as possible postinjury, preferably within the "golden hour." We have found that the best means to deliver estrogen is in a water-soluble form, given intravenously or intraosseously. Using a lateral fluid percussion model of traumatic brain injury (TBI) with rats, we demonstrate lessening of their injury when treated with soluble estradiol or ethinyl estradiol-3-sulfate. Magnetic resonance imaging reveals reduction of cerebral edema and anisotropy, while invasive measurements demonstrate reduced intracranial pressure, improved cerebral perfusion pressure, and partial brain oxygen pressure. Longer term benefits in cognition and memory have been shown with improved Morris Water Maze performance. Our promising results with TBI (and previously severe hemorrhage) encourage us to pursue application of ethinyl estradiol-3-sulfate for human use.