The present work holds value in both neuroscientific, as well as clinical terms. Our findings suggest a greater vulnerability of the female brain to stroke lesions affecting left-hemispheric posterior circulation regions. In particular, the implications of the observed female brain vulnerability may not be limited to stroke, but could also explain some of sex differences in other neuropsychiatric diseases, including Alzheimer’s disease. Our findings indicate that a sex-aware approach to the management of stroke may be justified to improve outcomes for both men and women. Further, our study paves the way for a novel line of research utilizing clinical sex differences (e.g., menopausal status) in diagnosis, treatment, rehabilitation and, ultimately, prevention of stroke. Lastly, our findings of novel sex-specific brain lesion patterns linked to post-stroke outcomes offer a unique and timely insight into mechanisms of brain resilience, and the opportunity to develop personalized approaches to the overall population brain health.