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Acute ischemic stroke affects men and women differently in many ways. In particular, women are oftentimes reported to experience a higher acute stroke severity than men. Here, we derived a low-dimensional representation of anatomical stroke lesions and designed a sex-aware Bayesian hierarchical modelling framework for a large-scale, well phenotyped stroke cohort. This framework was tailored to carefully estimate possible sex differences in lesion patterns explaining acute stroke severity (NIHSS) in 1,058 patients (39% female). Anatomical regions known to subserve motor and language functions emerged as relevant regions for both men and women. Female patients, however, presented a more widespread pattern of stroke severity-relevant lesions than male patients. Furthermore, particularly lesions in the posterior circulation of the left hemisphere underlay a higher stroke severity exclusively in women. These sex-sensitive lesion pattern effects could be discovered and subsequently robustly replicated in two large independent, multisite lesion datasets. The constellation of findings has several important conceptual and clinical implications: 1) suggesting sex-specific functional cerebral asymmetries, and 2) motivating a sex-stratified approach to management of acute ischemic stroke. To go beyond sex-averaged stroke research, future studies should explicitly test whether acute therapies administered on the basis of sex-specific cutoff volumes of salvageable tissue will lead to improved outcomes in women after acute ischemic stroke. ### Competing Interest Statement N.S.R. has received compensation as scientific advisory consultant from Omniox, Sanofi Genzyme and AbbVie Inc. * AIS : acute ischemic stroke MCA : middle cerebral artery NIHSS : National Institutes of Health Stroke Scale PCA : posterior cerebral artery

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