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Background: Of all subdivisions of stroke, intracerebral hemorrhagic stroke (ICH) only accounts for around 10-15% but is characterized by the highest mortality and morbidity. Lately, understanding immunological and inflammatory responses post-hemorrhagic stroke allows for the development of alternative therapeutic intervention. Toll-like receptors (TLR) are a large family of recognition receptors which have a regulatory pathway that is a key factor in determining the neurological outcomes of patients with ICH. In this study, we took a closer look at understanding the role that the overexpressing the soluble Toll-like receptor 4 (sTLR4) has on neuroprotection after ICH.Methods: Intracerebral injections of autologous blood were used to induce the ICH preclinical model on adeno-associated virus serotype 1 (rAAV1)-mediated FcV5 (control) and FcV5-sTLR4 expression in the brains of mice. Functional outcomes of these mice were assessed using several behavioral testing methods such as rotarod, open field locomotor test, and a neurological deficit score (NDS) at the different time-points of 24h, 48h and 72h. To assess changes to the lesion, hematoma and tissue injury, a histological stain, cresyl violet, was performed.Results: The data reveal a 41.9+/-8.2% smaller lesion volume in sTLR4 overexpressed mice. Further analysis with histological and immunochemical stains shows a trend towards a smaller tissue injury and hematoma volume, unchanged heme oxygenase 1 and iron levels, and unchanged microgliosis and astrogliosis levels.Conclusion: These findings reveal that the overexpression of sTLR4 does improve preliminary ICH outcomes. We will also discuss mechanisms behind the relationship between sTLR4 signaling and ICH along with possibilities of future methods of therapeutic interventions.