Abstract Body: Introduction: Women who smoke cigarettes while using oral contraceptives (OC) increase their risk for and severity of stroke compared to nonsmoking women who use OC. Studies published from our laboratory showed that combination of smoking derived nicotine (N) with OC exacerbates the severity of ischemic episodes in females via altering cerebral glucose and fatty acids metabolism. Relinquishing the smoking habit reduces the risk for stroke, however, N+OC withdrawal (NW) for 30 days fails to reduce severity of ischemic brain damage in female rats previously exposed to N+OC. The goal of the current study is to test the efficacy of an FDA-approved lipid-lowering drug Bezafibrate (Bez) in improving brain energy metabolism after nicotine withdrawal. Methods: Adult Sprague-Dawley female rats were randomly (n = 6-8/group) exposed to either saline, N (4.5 mg/kg) +/- OC for 16-21 days. To determine the effects of Bez along with N+OC on mitochondrial biogenesis, adult rats exposed to N+/-OC were fed ad libitum with either standard chow or 0.15% (w/w) bezafibrate-supplemented chow during 30 days of withdrawal period. At the end of the treatment, brain tissue was harvested to obtain an unbiased global metabolomic profile (performed by Metabolon Inc.) The metabolomic study was complemented with western blot analysis and enzyme activity measurements of key altered pathways. Mitochondrial biogenesis was assessed by western blots of oxidative phosphorylation system subunits and by enzymatic determination of complex activities and citrate synthase. Results: Global metabolomic analysis showed that several of the long chain polyunsaturated fatty acids (LCPUFAs) (e.g., docosahexaenoate (DHA; 22:6n3) and arachidonate (20:4n6)) were significantly higher in the N+Bez, OC+Bez, and N+OC+Bez groups when compared to the nicotine group. It is shown that Bez decreases serum lipid levels by activating cellular uptake of fatty acids. These results suggest that Bez treatment is increasing cortical tissue uptake of LCPUFAs in the N and N+OC groups. Enzymatic analysis of electron transport chain complexes showed the activities of NADH dehydrogenase and cytochrome c oxidase were significantly higher in N+Bez and Sal+Bez when compared to nicotine group. Conclusion: Bezafibrate could potentially mitigate effects of N+OC on the brain and rescue cerebral energy metabolism. Future studies are needed to evaluate it’s impact on stroke outcomes.