Each year more than 1.7 million individuals experience a traumatic brain injury (TBI) in the United States. Although women comprise nearly 25% of this population, gender-specific outcomes after TBI in regards to pathophysiology, response to therapeutic treatments and recovery have been studied to a limited extent (1). Clinical studies assessing patient recovery after TBI have been contradictory with some studies suggesting better outcomes whilst others suggesting poorer long-term outcomes in women compared to men. In animal studies, brains of female rodents appear to have an innate neuroprotection against injury compared to their injured male counterparts. The following study aims to document pathophysiological differences by providing a more comprehensive analysis of the gender response to TBI. Using a lateral fluid percussion (LFP) brain injury model, pathological outcomes such as neurodegeneration, traumatic axonal injury (TAI) and reactive gliosis were evaluated. The results showed a gender-associated attenuation of TAI in female rats post-injury. However, injured female rats presented with significantly greater degenerating neurons within the ventrobasal thalamus, but not in other thalamic nuclei compared to injured male rats. Sex did not significantly influence the activation of either astrocytes or microglia post-injury. Progesterone is currently undergoing clinical trials as a potential therapeutic against TBI because of its ability to exert pleiotropic neuroprotection against brain injury. Gender-associated differences in progesterone treatment efficacy have yet to be thoroughly evaluated even though women have been reported to be at a greater risk of developing adverse reactions to therapeutic drugs compared to men (33). With that in mind, we proceeded to evaluate the gender-specific differences of progesterone treatment against TBI. Sprague Dawley rats subjected to a LFP injury were treated with 16mg/kg of progesterone at 6hr post injury and subsequently for the next 5 consecutive days. Progesterone treatment attenuated reactive astrogliosis along the cortex in females but not in males. These pathological alterations occurred in the absence of any observable differences in TAI, neurodegeneration, microglial activation after progesterone intervention. Progesterone treated injured males did not differ from vehicle treated males after injury. Supplemental studies regarding the treatment regimen and dosing is required in assessing progesterone’s effectiveness against LFP injury before any conclusive statements can be made.