Abstract Body: Introduction: IL-6 is a pro-inflammatory cytokine typically low in healthy young individuals but elevated after stroke, correlating with worse outcomes. IL-6 binds to soluble IL-6 receptors, which then interact with the glycoprotein gp130, initiating pro-inflammatory trans-signaling. In young mice, gp130Fc administration showed dose-dependent benefits. To test this in older individuals, gp130Fc (0.5 mg/kg, intraperitoneally) was given to aged mice 4 hours after middle cerebral artery occlusion. This dose caused 80% mortality in aged males within 72 hours, while all females survived. A lower dose (0.25 mg/kg) improved survival to 70% in aged males. Aged females had higher baseline plasma IL-6, which may explain their higher dose tolerance. Aging is associated with cognitive decline, leading us to hypothesize that inhibiting IL-6 trans-signaling could improve cognitive function in older animals. Methods: Aged (18-19 months) C57BL/6 male and female mice were used to assess cognitive deficits following gp130Fc treatment. The mice received either saline or gp130Fc at doses of 0.25 mg/kg (for males) and 0.5 mg/kg (for females) via intraperitoneal injection a week before behavioral testing and at day 14. Cognitive function was evaluated using several tests: Y-Maze on day 7, Novel Object Recognition Test (NORT) on day 14, and Object Location (OL) on day 21. From days 22-26, mice underwent training on the Barnes Maze, with testing on day 27. Mice were euthanized on day 28. Results: Older animals exhibited similar deficits in short-term memory as assessed on the Y maze, NORT, and OL task regardless of sex, but aged females showed worse long-term memory retention compared to age-matched males, as assessed by the Barnes Maze. Female mice took longer to escape and made more incorrect entries (P<0.05) than males. Inhibition of peripheral IL-6 trans-signaling worsened (P<0.05) long-term memory retention in aged males compared to vehicle-treated animals, whereas gp130Fc treatment improved long-term memory retention in aged females. Conclusion: This study demonstrates that aged female mice exhibit more pronounced cognitive impairments than their male counterparts. Inhibition of IL-6 trans-signaling with gp130Fc ameliorates cognitive deficits in aged females but exacerbates cognitive decline in aged males.