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Atrial fibrillation (AF) is considered a predictive factor of poor clinical outcome in patients with an ischemic stroke (IS). This study addressed whether the impact of AF on the in-hospital mortality after first ever IS is different according to the patient's gender.We prospectively studied 1678 patients with first ever IS consecutively admitted to two University Hospitals. We recorded demographic data, vascular risk factors, and the stroke severity (NIHSS) at admission analyzing their impact on the in-hospital mortality and on the combined mortality-dependency at discharge using a Cox proportional hazards model. Two variable interactions between those factors independently related to in-hospital mortality and combined mortality-dependency at discharge were tested.Overall in-hospital mortality was 11.3%. Cox proportional hazards model showed that NIHSS at admission (HR: 1.178 [95% CI 1.149-1.207]), age (HR: 1.044 [95% CI 1.026-1.061]), AF (HR: 1.416 [95% CI 1.048-1.913]), male gender (HR: 1.853 [95% CI 1.323-2.192) and ischemic heart disease (HR: 1.527 [95% CI 1.063-2.192]) were independent predictors of in-hospital mortality. A significant interaction between gender and AF was found (p = 0.017). Data were stratified by gender, showing that AF was an independent predictor of poor outcome just for woman (HR: 2.183 [95% CI 1.403-3.396]; p < 0.001). The independent predictors of combined mortality-disability at discharge were NIHSS at admission (HR: 1.052 [95% CI 1.041-1.063]), age (HR: 1.011 [95% CI 1.004-1.018]), AF (HR: 1.197 [95% CI 1.031-1.390]), ischemic heart disease (HR: 1.222 [95% CI 1.004-1.488]), and smoking (HR: 1.262 [95% CI 1.033-1.541]).The impact of AF is different in the twogenders and appears as a specific ischemic stroke predictor of in-hospital mortality just for women.