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Intracerebral hemorrhage (ICH) has the highest morbidity, disability, and mortality rates of any stroke subtype, including ischemic stroke. When a hemorrhagic stroke occurs, the blood-brain barrier is broken and blood components enter the brain. A major cause of morbidity and mortality following ICH is the direct toxicity of blood metabolites, notably free heme, on adjacent brain tissue. Hemopexin (Hpx) is the endogenous protein responsible for scavenging free heme; thereby, modulating its proxidant and proinflammatory properties. Given the low relative level of Hpx expression in the brain, we hypothesized that overexpression of Hpx would improve anatomical and functional outcomes after ICH. Unique adeno-associated viral vectors (and control vectors) were designed to specifically overexpress Hpx-(tags) locally within the brain. Hpx-overexpressing mice have smaller lesion volumes (p<0.05) and reduced blood accumulation (p<0.05) at 72h post-ICH (n=12-13/group). Improved anatomical outcomes are also associated with better neurologic functional recovery as measured by a 24-point neurological deficit scale (p<0.05). Histological staining for ferric iron, 4-hydroxynonenal, GFAP, Iba-1, heme oxygenase-1, and myeloperoxidase was performed and the distribution of Hpx-tag proteins was evaluated by Western blotting with anti-tag probing of brain homogenates, cerebrospinal fluid, and serum. Hpx-overexpressing mice have significantly increased cortical microgliosis and astrogliosis and peripheral neutrophil infiltration, but no changes in striatal microgliosis and astrogliosis, ferric iron content, heme oxygenase-1 expression, or lipid peroxidation. Additionally, Hpx-tag proteins were highly expressed in all three types of biological specimens evaluated. The increased levels of Hpx in the serum of Hpx-overexpressing mice were confirmed to be 62% higher by ELISA (p<0.01). These results indicate that the local overexpression of Hpx in the brain results in the capacity to facilitate the clearance of heme likely by central and peripheral mechanisms. Specific modulation of local Hpx levels may represent a clinically relevant strategy for the treatment of secondary brain injury following ICH.