Abstract Body: Receptor-interacting serine-threonine protein kinase 2 (Ripk2) is a key enzyme in inflammatory signaling. Ripk2 has been shown to act through pattern recognition receptors that respond to bacterial endotoxins and damage-associated molecular patterns, triggering inflammatory cascades including TAK1, NF-κB, and MAPK pathways. Recent work has implicated Ripk2 as a therapeutic target in several inflammatory disease states, such as inflammatory bowel disease and autoimmune diseases like lupus and multiple sclerosis. In our lab, we have shown that Ripk2 contributes to secondary injury following ischemic stroke due to neuroinflammation. Previous work in our lab has shown that both global knockout and microglia-specific knockout of Ripk2 in young mice are protective following stroke, resulting in smaller infarct size and fewer neurological deficits. Additionally, pharmacologically inhibiting Ripk2 is neuroprotective and reduces infarction and deficits after stroke. However, the impact of Ripk2 deficiency on stroke outcomes in aged mice is unknown. We utilized Ripk2 knockout (Ripk2^-/-) mice and wildtype (WT) mice (19-20 months old) and subjected them to permanent middle cerebral artery occlusion (pMCAO). Behavior tests were conducted for 28 days following pMCAO for longitudinal assessment of Ripk2 deficiency on sensorimotor and cognitive deficits. These included the open field test, weight grip test, vertical grid test, novel object recognition test, cylinder test, and Y-maze. Ripk2^-/- mice performed better than WT controls on the vertical grid test on days 1, 3, 8, 15, and 22 (p<0.05, two-way ANOVA with Šídák’s post-hoc). Ripk2^-/- mice also had higher scores on the weight grip test compared to WT controls on days 3, 8, 15, and 22 (p<0.05, two-way ANOVA with Šídák’s post-hoc). Mice were sacrificed on day 28 following pMCAO for infarct size measurement and histology. While there was a trend toward smaller infarcts in Ripk2^-/- mice compared to WT mice at 28 days after stroke (p=0.0978), we found no statistically significant differences between groups in open field test, novel object recognition, cylinder test, or Y-maze. Experiments are ongoing to assess effects of Ripk2 deficiency on microgliosis and astrogliosis in the ipsilateral hemisphere in brain sections. Our results significantly contribute to our understanding of the role that Ripk2 plays in ischemic stroke pathology by incorporating aged animals and long-term analyses of anatomical and behavioral outcomes.