Traumatic brain injury (TBI) is a leading cause of death and cognitive disability and is a known risk of military service. Women constitute a large share of servicemembers seeking care from the Veterans Health Administration. Women servicemembers, especially those involved in recent conflicts, smoke at significantly higher rates than civilian women. Along with smoking, women servicemembers are also likely to use oral contraceptives (OC), owing to their reproductive age. However, what impact the simultaneous usage of OC and smoking will have on outcome after mild TBI (mTBI) remains to be investigated. Research conducted during the last decade in our laboratory demonstrated that simultaneous exposure to smoking derived-nicotine (N) and OC (N+OC) as short as three weeks renders reproductive-age female rats more susceptible to secondary brain injury. N+OC exposure impedes estrogen receptor subtype beta (ER-β)-mediated mitochondrial function by interfering with electron transport chain complex IV (CIV) activity and increases inflammasome activation in the brain. The current study aims to test whether observed loss of ER-β-mediated CIV activity, induction of inflammation, and subsequent stress on brain energy metabolism due to N+OC exposure leads to worsened post-mTBI secondary brain injury and cognitive decline. Cognitive decline is one of the major consequences of mTBI and what effects the combination of N+OC has on post-mTBI cognition needs investigation. Pilot data showing that nicotine itself or nicotine-containing electronic cigarette (EC) exposure combined with OC results in deleterious effects on cognitive capacities including spatial learning and memory in female rats leads us to test in this study whether post-TBI declines in cognition are made even worse by N/EC+OC exposure. The successful completion of proposed study will characterize the effects of N+OC on mTBI-induced neurodegeneration and cognitive decline and will fill a current gap in knowledge on secondary brain injury after mTBI in women.