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Background and Purpose: Age and sex have important effects on stroke-induced inflammation. We conducted CBC analysis and RNA-sequencing of ischemic stroke patient blood, with follow-up studies in an experimental mouse model, to test the hypothesis that there are sex differences in neutrophil function and neutrophil-mediated damage after ischemic stroke.Methods: Blood from male and female stroke patients was collected 24 hours after stroke, with transient ischemic attack patients serving as controls. Absolute neutrophil count was quantified and RNA-sequencing was performed on an age and severity matched subset of patients. Results were analyzed by multivariate regression and differential expression analysis, respectively. For animal experiments, aged (18-20 month) and young (8-10 week) male and female mice were subjected to 60 minute middle cerebral artery occlusion and sacrificed at 24 hours. Neutrophils from blood, bone marrow, lung, brain and spleen were quantified and phenotyped by flow cytometry. Results were analyzed by student T-test and two way ANOVA.Results: Absolute neutrophil counts increased significantly after stroke in both sexes (p=.01). Interestingly, females had more differentially expressed genes after stroke than males, including matrix metalloproteinase 9 and TNFa. In animal experiments, aged animals were found to have higher percentages of neutrophils in the blood, spleen, lungs and bone marrow than young animals. In addition, aged female animals were found to have more activated neutrophils 24 hours after stroke than aged males (p=<.05).Conclusion: These results suggest that the immune response to ischemic stroke differs in aged males and females. Female neutrophils appear to exhibit enhanced activation, which may contribute to the poorer stroke outcomes seen in aged female patients. Understanding sex and age differences in the acute immune response is crucial to developing future immunomodulatory drugs for the safe and effective treatment of ischemic stroke in both sexes.