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Male and female nervous systems respond differently to traumatic brain injury (TBI) and in vivo research relates this difference to neuroprotection from female sex hormones. Attempts to replicate female sex hormone-related neuroprotection in clinical studies have been unsuccessful. The objective of this study was to determine whether gender or menopausal status affects mortality in patients with moderate to severe TBI.A retrospective review of all patients with isolated moderate to severe TBI was undertaken using data from the National Trauma Database version 6.2 (2000–2005). Isolated TBI was defined as head Abbreviated Injury Score ≥3 in patients without significant extracranial injuries (Abbreviated Injury Score <3 for other anatomic regions). Demographics, Injury Severity Score, and outcomes (mortality, intensive care unit and hospital length of stay, and complications) were compared. The population was stratified into age subgroups: 14 to 45 years (premenopausal), 46 to 55 years (perimenopausal), and older than 55 years (postmenopausal). Logistic regression analysis was used to determine the relationship among female gender, mortality, and development of complications after moderate to severe TBI.A total of 72,294 patients with moderate to severe TBI were evaluated. Females showed a significantly lower risk in both mortality (adjusted odds ratios [AOR], 0.82; 95% confidence intervals [CI], 0.77–0.87; p < 0.0001) and in developing any type of complications (AOR, 0.88; 95% CI, 0.84–0.93; p < 0.0001) than the male population after adjusting for differences in patient characteristics. After age stratification, perimenopausal women (46–55 years) and postmenopausal women (older than 55 years) showed a significantly lower risk in mortality (AOR, 0.76; 95% CI, 0.63–0.92; p < 0.0044 and AOR, 0.79; 95% CI, 0.73–0.86; p < 0.0001, respectively). There was no difference in mortality in premenopausal women compared with their male age-matched counterparts (AOR, 1.09; 95% CI, 0.99–1.21; p = 0.0917).Female gender is independently associated with reduced mortality and decreased complications after TBI. As peri- and postmenopausal women demonstrated improved survival, and premenopausal women did not, estrogen unlikely confers neuroprotection in women after TBI. Future TBI treatment may benefit with further research focused on why peri- and postmenopausal women show decreased mortality after TBI.