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Background: Literature has highlighted sex-based differences in the natural course of stroke and in response to treatment with intravenous tissue plasminogen activator (tPA). Objectives: We aimed to compare the management and outcome of acute ischemic stroke (AIS) among women and men on a French registry based on a federated network of emergency physicians and neurologists. Method: We included 2,790 patients received tPA between 2010 and 2016 from the stroke centers in the RESUVal area. We provided age-adjusted analysis and multivariate models for determining the role of sex in the outcome measures. Results: After age-adjustment, women presented more moderate to severe stroke at admission with more proximal occlusions. Among tPA eligible patients, the therapeutic strategy and in-hospital hemorrhagic complications were proportionally identical whatever the sex. The total ischemic time from onset symptom to thrombolysis did not differ from women to men. Age-adjusted 3-month mortality did not differ between women and men, and the determinants of mortality were age (relative risk [RR] 1.56 [1.37–1.78], p < 0.0001), proximal occlusion (RR 2.5 [1.88–3.33], p < 0.0001), and at least one complication (RR 2.43 [1.89–3.13], p < 0.0001). The determinants of poor functional outcome at 3 months were the sex (RR 1.22 [1.01–1.48] for women, p = 0.0385) and the occurrence of onset symptom in rural landscape (RR 1.26 [1.03–1.55], p = 0.0219) compared to urban landscape. Conclusions: We provided an exhaustive overview and real-life professional practices conditions in thrombolyzed AIS. Despite a later prehospital management in neurovascular units and more severe strokes at admission, women and men had both similar outcomes at hospital discharge and in 3-month survival, but women were associated to worst functional outcome at 3 months. [ABSTRACT FROM AUTHOR]