Abstract Body: Background: Elevated circulating IL-6 levels are associated with poor outcomes following stroke, and increased serum IL-6 levels correlate with worse stroke outcomes. IL-6 binds to soluble IL-6 receptors, binding to ubiquitously expressed gp130 to initiate proinflammatory trans-signaling. This exploratory study investigates the impact of inhibiting IL-6 trans-signaling on long-term functional outcomes in ischemic stroke. Methods: Young mice (8-15 weeks old) were administered recombinant saline/gp130Fc an IL-6 trans-signaling inhibitor, twice a week for two weeks, starting at the time of reperfusion after 60 minutes of post-middle cerebral artery occlusion (MCAO). Neurological deficit scores and infarct volumes were assessed at 24 hours, with long-term cognitive and motor evaluations conducted at 7 and 28 days post-MCAO. Gliosis and neurogenesis were analyzed via fluorescence microscopy, and plasma IL-6 levels were quantified using ELISA. Flow cytometry was performed to assess membrane IL-6 receptor and IL-6 levels on immune cells in the blood and brain at 24,72 hours and 7 days post-MCAO. Results: MCAO in young male mice significantly increased IL-6 expression while acutely reducing membrane IL-6 receptor levels in peripheral immune cells. Treatment with gp130Fc (0.5 mg/kg) effectively improved neurological deficit scores (NDS) and reduced infarct volume (p<0.05) at 24 hours post-stroke in male mice. This inhibition of IL-6 trans-signaling also mitigated cognitive decline and decreased tissue loss, inflammation, and SVZ IL-6 levels at sub-acute and chronic stages. In contrast, female mice did not improve cognitive function, tissue preservation, or neuroinflammation with the same treatment. Interestingly, female mice exhibited higher systemic IL-6 levels and elevated IL-6 expression on monocytes and neutrophils 24 hours post-stroke compared to age-matched sham controls. A higher dose of gp130Fc (1 mg/kg) was required to achieve significant neurological improvement and infarct reduction in female mice. Conclusion: These findings highlight the beneficial effects of inhibiting IL-6 trans-signaling with gp130Fc in both male and female mice. This demonstrates a clear dose-dependent response, with a higher dose needed for efficacy in females.