ABSTRACT Females comprise 41% of annual cases of traumatic brain injury (TBI). Further, when the rate of injury is compared, female TBI is either the same or higher than males, indicating a unique vulnerability of females. In addition, rates of both incidence and hospitalization have significantly increased over the past decade in females and growing numbers are likely attributed to increased participation in combat and collision sports and military enrollment. Despite the high number of injuries, little has been done to study factors that may make females more susceptible to injury and the specific constellation of symptoms they experience. This may be due in part to the prevailing opinion that female reproductive hormones are neuroprotective against TBI. Pre-clinical work has strongly demonstrated that females have better outcomes following injury, although when care is taken to properly normalize data, females commonly have the same or worse outcomes than males. Clinically, studies have shown contradictory results and differences may be due to choice of timepoints and outcome measures used that do not consider biopsychosocial aspects and gender-based expectations. While pre-injury levels of reproductive hormones have been of interest, few studies have looked at the role of sex-hormones post-injury in females. Hormonal dysfunction following TBI is a well-established phenomenon and likely has a large role in recovery and outcome. Less established is how changes in regulation of these hormones may influence sex-specific symptomatology including pain and affective disorders. Neuroplasticity, mood and learning are associated with menstrual-cycle stage and disruptions in hormonal patterns negatively affect these domains. Pre-clinical work has shown that both stress and sex-hormones are disrupted acutely and chronically following TBI. Our work shows evidence of perturbed cerebral metabolism and abnormal changes in affective and nociceptive behaviors. The central premise of this proposal is that female sex- hormones (1) modulate cerebral metabolism at the time injury, contributing to initial injury severity and (2) changes in the regulation and production of female sex-hormones are responsible for sex-specific difference in symptomology post-injury. The current proposed aims will identify pre- and post-injury variables and mechanisms that make females more susceptible to 1) TBI and 2) prolonged recovery and differential outcomes compared to males. The research findings from these aims are critical to understanding sex-based differences to develop sex-specific therapeutic interventions.